SynGap Missense Server

Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.

c.dna Variant SGM Consensus Domain ClinVar gnomAD ESM1b AlphaMissense REVEL FoldX Rosetta Foldetta PremPS PROVEAN PolyPhen-2 HumDiv PolyPhen-2 HumVar FATHMM SIFT PAM Physical SASA Normalized B-factor backbone Normalized B-factor sidechain SynGAP Structural Annotation DOI
Clinical Status Review Subm. ID Allele count Allele freq. LLR score Prediction Pathogenicity Class Optimized Score Prediction Average ΔΔG Prediction StdDev ΔΔG Prediction ΔΔG Prediction ΔΔG Prediction Score Prediction pph2_prob Prediction pph2_prob Prediction Nervous System Score Prediction Prediction Status Conservation Sequences PAM250 PAM120 Hydropathy Δ MW Δ Average Δ Δ StdDev Δ StdDev Secondary Tertiary bonds Inside out GAP-Ras interface At membrane No effect MD Alert Verdict Description
c.2750C>GP917RLikely BenignUncertain 16-33443302-C-G53.10e-6-4.475Likely Benign0.363AmbiguousLikely Benign0.142Likely Benign-1.70Neutral0.642Possibly Damaging0.316Benign2.68Benign0.00Affected3.775-20-2.959.07
c.280C>TP94SLikely BenignBenign 16-33425888-C-T53.10e-6-3.151Likely Benign0.084Likely BenignLikely Benign0.093Likely Benign-2.36Neutral0.092Benign0.008Benign4.13Benign0.00Affected4.3211-10.8-10.04
c.2818G>CG940RLikely BenignBenign 16-33443370-G-C53.10e-6-6.169Likely Benign0.480AmbiguousLikely Benign0.060Likely Benign0.02Neutral0.922Possibly Damaging0.543Possibly Damaging2.73Benign0.15Tolerated3.775-3-2-4.199.14
c.286G>AG96SLikely BenignUncertain 16-33425894-G-A53.10e-6-3.049Likely Benign0.065Likely BenignLikely Benign0.071Likely Benign-0.76Neutral0.364Benign0.008Benign4.25Benign0.00Affected4.32110-0.430.03
c.3254G>AR1085QLikely BenignUncertain 16-33443806-G-A53.16e-6-3.843Likely Benign0.589Likely PathogenicLikely Benign0.224Likely Benign-1.43Neutral0.998Probably Damaging0.988Probably Damaging2.73Benign0.02Affected3.775111.0-28.06
c.3862A>GK1288EUncertain 16-33447910-A-G53.22e-6-2.751Likely Benign0.407AmbiguousLikely Benign0.185Likely Benign-3.27Deleterious0.979Probably Damaging0.973Probably Damaging2.13Pathogenic0.00Affected3.775100.40.94
c.3902C>AP1301HLikely BenignConflicting 26-33451776-C-A53.10e-6-5.756Likely Benign0.104Likely BenignLikely Benign0.232Likely Benign-1.13Neutral0.642Possibly Damaging0.378Benign2.79Benign0.04Affected3.7750-2-1.640.02
c.3970C>TP1324SLikely BenignLikely Benign 16-33451844-C-T53.26e-6-5.451Likely Benign0.068Likely BenignLikely Benign0.049Likely Benign0.35Neutral0.225Benign0.092Benign4.33Benign0.00Affected4.3211-10.8-10.04
c.404G>AR135QUncertain 16-33432701-G-A53.84e-6-8.011Likely Pathogenic0.853Likely PathogenicAmbiguous0.087Likely Benign-1.94Neutral0.327Benign0.100Benign3.76Benign0.02Affected3.615111.0-28.06
c.455G>AR152QUncertain 16-33432752-G-A53.14e-6-10.336Likely Pathogenic0.989Likely PathogenicLikely Pathogenic0.181Likely Benign-2.34Neutral0.997Probably Damaging0.968Probably Damaging3.89Benign0.00Affected3.615111.0-28.06
c.892C>TP298S
(3D Viewer)
Likely BenignC2Benign 16-33437797-C-T53.10e-6-6.342Likely Benign0.144Likely BenignLikely Benign0.189Likely Benign1.38Ambiguous0.21.41Ambiguous1.40Ambiguous0.58Ambiguous-1.20Neutral0.991Probably Damaging0.898Possibly Damaging2.03Pathogenic0.85Tolerated3.3920-110.8-10.04
c.1118G>TG373V
(3D Viewer)
Likely BenignC2Uncertain 16-33438023-G-T65.03e-6-6.062Likely Benign0.112Likely BenignLikely Benign0.428Likely Benign5.32Destabilizing3.20.82Ambiguous3.07Destabilizing0.09Likely Benign-0.98Neutral0.007Benign0.001Benign3.90Benign0.00Affected3.5316-1-34.642.08207.6-68.11.91.1-0.60.1UncertainGly373 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val373 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on the Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn.
c.1213C>TR405C
(3D Viewer)
Likely PathogenicC2Conflicting 26-33438118-C-T63.72e-6-9.206Likely Pathogenic0.713Likely PathogenicLikely Benign0.427Likely Benign0.72Ambiguous0.11.51Ambiguous1.12Ambiguous1.21Destabilizing-7.27Deleterious1.000Probably Damaging1.000Probably Damaging3.61Benign0.02Affected3.3828-4-37.0-53.05221.382.6-0.10.0-0.20.3XXPotentially PathogenicThe guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Ala399-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the thiol-containing side chain of Cys405 is neutral and smaller compared to the arginine side chain. The lack of Arg405-Phe358 stacking affects the loop structure, causing it to assume a β strand form—an effect that could be exacerbated during protein folding. Moreover, the inability of Cys405 to form a salt bridge with Glu446 could affect the tertiary structure assembly, although this is not apparent based on the variant simulations.
c.2207G>AR736HLikely BenignUncertain 16-33441672-G-A63.72e-6-5.409Likely Benign0.067Likely BenignLikely Benign0.029Likely Benign-0.12Neutral0.004Benign0.001Benign2.50Benign0.00Affected4.073201.3-19.05
c.1729G>AA577T
(3D Viewer)
Likely BenignGAPBenign 16-33440781-G-A63.72e-6-5.311Likely Benign0.322Likely BenignLikely Benign0.427Likely Benign0.86Ambiguous0.10.54Ambiguous0.70Ambiguous0.54Ambiguous-1.47Neutral0.999Probably Damaging0.987Probably Damaging-1.31Pathogenic0.47Tolerated3.373410-2.530.03191.9-43.40.00.00.70.1XPotentially BenignAla577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. In the variant simulations, the hydroxyl group of the Thr577 side chain hydrogen bonds with the backbone atoms of Arg573 and Lys574 within the same helix, which has the potential to weaken the stability of the secondary structure element. Regardless, the residue swap seems to be well tolerated based on the variant simulations.
c.2218C>TR740WUncertain 26-33441683-C-T63.72e-6-8.561Likely Pathogenic0.168Likely BenignLikely Benign0.180Likely Benign-3.09Deleterious1.000Probably Damaging0.938Probably Damaging2.52Benign0.01Affected4.3222-33.630.03
c.2224C>TR742WLikely BenignUncertain 16-33441689-C-T63.72e-6-7.725In-Between0.133Likely BenignLikely Benign0.079Likely Benign-1.71Neutral0.992Probably Damaging0.684Possibly Damaging2.66Benign0.01Affected4.322-323.630.03
c.2255C>TS752LLikely BenignUncertain 26-33441720-C-T63.72e-6-3.386Likely Benign0.182Likely BenignLikely Benign0.195Likely Benign-2.09Neutral0.993Probably Damaging0.641Possibly Damaging1.51Pathogenic0.01Affected3.995-3-24.626.08
c.1786C>TR596C
(3D Viewer)
Likely PathogenicGAPConflicting 26-33440838-C-T63.72e-6-10.805Likely Pathogenic0.972Likely PathogenicLikely Pathogenic0.633Likely Pathogenic2.94Destabilizing0.01.49Ambiguous2.22Destabilizing-0.03Likely Benign-7.96Deleterious1.000Probably Damaging1.000Probably Damaging2.41Pathogenic0.00Affected3.3735-4-37.0-53.05230.797.9-0.10.0-0.30.4XXPotentially PathogenicThe guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the thiol group of the Cys596 side chain is unable to form salt bridges or any of the hydrogen bonds that the Arg596 side chain can. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation.
c.2349G>AM783ILikely BenignBenign 16-33442901-G-A63.72e-6-3.560Likely Benign0.418AmbiguousLikely Benign0.042Likely Benign-0.54Neutral0.004Benign0.006Benign2.87Benign0.22Tolerated3.646122.6-18.03
c.1811C>TS604L
(3D Viewer)
Likely PathogenicGAPUncertain 16-33440863-C-T63.72e-6-14.683Likely Pathogenic0.965Likely PathogenicLikely Pathogenic0.639Likely Pathogenic-0.94Ambiguous0.1-1.24Ambiguous-1.09Ambiguous-0.31Likely Benign-5.97Deleterious1.000Probably Damaging0.991Probably Damaging3.09Benign0.00Affected3.3735-3-24.626.08234.0-49.60.00.10.30.5XXPotentially PathogenicSer604 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). In the WT simulations, the hydroxyl side chain of Ser604 periodically hydrogen bonds with the backbone carbonyl groups of other α helix residues (e.g., Pro600, Met603). Serine weakens the α helix secondary structure, and thus, Ser604 along with Pro605 breaks the α helix, facilitating the turn in the WT structure.In contrast, in the variant simulations, Leu604 forms a few hydrophobic interactions (e.g., Leu607, Phe608). More importantly, the helix end is more stable than with Ser604 in the WT. The residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end, than what the simulations suggest.Moreover, Ser604 directly hydrogen bonds with Ras residues Ser65 and Ala66 in the WT SynGAP-Ras complex. The hydrophobic leucine cannot maintain these interactions with Ras at the GAP-Ras interface. Thus, the effect of the residue swap on the complex formation with the GTPase cannot be fully explored in the solvent-only simulations.
c.2393C>TP798LLikely BenignSH3-binding motifUncertain 26-33442945-C-T63.72e-6-5.640Likely Benign0.074Likely BenignLikely Benign0.042Likely Benign-0.86Neutral0.981Probably Damaging0.631Possibly Damaging4.21Benign0.00Affected4.321-3-35.416.04
c.2591C>TA864VLikely BenignUncertain 26-33443143-C-T63.72e-6-4.749Likely Benign0.126Likely BenignLikely Benign0.038Likely Benign-1.35Neutral0.767Possibly Damaging0.119Benign2.45Pathogenic0.30Tolerated3.824002.428.05
c.2681G>AG894ELikely BenignUncertain 16-33443233-G-A63.72e-6-5.377Likely Benign0.859Likely PathogenicAmbiguous0.180Likely Benign-2.07Neutral1.000Probably Damaging1.000Probably Damaging2.68Benign0.01Affected4.3240-2-3.172.06
c.2695A>GI899VLikely BenignBenign 16-33443247-A-G63.72e-6-2.569Likely Benign0.074Likely BenignLikely Benign0.040Likely Benign0.09Neutral0.220Benign0.078Benign2.75Benign0.92Tolerated4.32443-0.3-14.03
c.2924C>TT975ILikely BenignUncertain 16-33443476-C-T63.72e-6-3.912Likely Benign0.164Likely BenignLikely Benign0.068Likely Benign-1.66Neutral0.411Benign0.239Benign4.11Benign0.66Tolerated4.3220-15.212.05
c.2948G>AS983NLikely Benign 16-33443500-G-A63.72e-6-5.604Likely Benign0.909Likely PathogenicAmbiguous0.136Likely Benign-1.78Neutral0.991Probably Damaging0.988Probably Damaging2.04Pathogenic0.00Affected4.32111-2.727.03
c.3181G>TG1061CLikely BenignConflicting 26-33443733-G-T63.73e-6-9.511Likely Pathogenic0.119Likely BenignLikely Benign0.409Likely Benign-1.46Neutral0.938Possibly Damaging0.665Possibly Damaging3.97Benign0.00Affected4.322-3-32.946.09
c.323A>GK108RLikely BenignUncertain 16-33432188-A-G63.72e-6-2.892Likely Benign0.148Likely BenignLikely Benign0.184Likely Benign0.37Neutral0.993Probably Damaging0.956Probably Damaging4.22Benign1.00Tolerated3.61532-0.628.01
c.3293G>AS1098NLikely BenignConflicting 26-33443845-G-A63.89e-6-5.120Likely Benign0.156Likely BenignLikely Benign0.063Likely Benign-0.58Neutral0.369Benign0.120Benign2.76Benign0.36Tolerated3.77511-2.727.03
c.3307C>TR1103CUncertain 16-33443859-C-T63.92e-6-2.440Likely Benign0.246Likely BenignLikely Benign0.140Likely Benign-3.01Deleterious0.996Probably Damaging0.787Possibly Damaging2.41Pathogenic0.01Affected3.775-3-47.0-53.05
c.3313C>TR1105WUncertain 16-33443865-C-T63.93e-6-6.911Likely Benign0.488AmbiguousLikely Benign0.133Likely Benign-4.34Deleterious0.999Probably Damaging0.696Possibly Damaging2.42Pathogenic0.02Affected3.775-323.630.03
c.380G>AR127QLikely BenignUncertain 16-33432245-G-A63.72e-6-1.711Likely Benign0.320Likely BenignLikely Benign0.037Likely Benign-1.04Neutral0.006Benign0.001Benign4.04Benign0.02Affected3.744111.0-28.06
c.4006G>AE1336KLikely BenignBenign 26-33451880-G-A64.20e-6-4.697Likely Benign0.977Likely PathogenicLikely Pathogenic0.272Likely Benign-2.44Neutral0.748Possibly Damaging0.079Benign3.23Benign0.00Affected3.77501-0.4-0.94
c.73C>TR25WLikely BenignUncertain 26-33423482-C-T63.72e-6-5.133Likely Benign0.549AmbiguousLikely Benign0.158Likely Benign-1.60Neutral0.994Probably Damaging0.919Probably Damaging3.92Benign0.00Affected4.321-323.630.03
c.707C>TA236V
(3D Viewer)
PHBenign/Likely benign 26-33435558-C-T63.72e-6-8.752Likely Pathogenic0.267Likely BenignLikely Benign0.777Likely Pathogenic0.61Ambiguous0.21.08Ambiguous0.85Ambiguous0.64Ambiguous-3.55Deleterious0.981Probably Damaging0.446Benign5.79Benign0.03Affected3.4014002.428.05213.8-44.70.00.0-0.20.2XPotentially BenignThe methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations.
c.958G>CV320L
(3D Viewer)
C2Uncertain 16-33437863-G-C63.72e-6-6.207Likely Benign0.362AmbiguousLikely Benign0.096Likely Benign-0.26Likely Benign0.21.33Ambiguous0.54Ambiguous0.51Ambiguous-1.02Neutral0.900Possibly Damaging0.373Benign1.78Pathogenic0.92Tolerated3.382321-0.414.03245.8-10.20.30.90.10.3XPotentially BenignThe isopropyl side chain of Val310, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), hydrophobically packs with the side chains of nearby residues (e.g., Leu286, Val350, Pro318). The hydrophobic Leu320 side chain mostly forms the same interactions; hence, the residue swap does not seem to negatively affect the protein structure based on the variant simulations.
c.121C>TR41CLikely BenignConflicting 36-33423530-C-T74.34e-6-4.745Likely Benign0.207Likely BenignLikely Benign0.093Likely Benign-1.10Neutral0.976Probably Damaging0.919Probably Damaging4.13Benign0.00Affected4.321-4-37.0-53.05
c.1436G>AR479Q
(3D Viewer)
Likely BenignGAPUncertain 16-33438468-G-A74.34e-6-7.109In-Between0.259Likely BenignLikely Benign0.191Likely Benign0.54Ambiguous0.10.57Ambiguous0.56Ambiguous0.49Likely Benign-1.16Neutral1.000Probably Damaging0.991Probably Damaging3.42Benign0.31Tolerated3.3932111.0-28.06
c.1610C>TA537V
(3D Viewer)
Likely BenignGAPLikely Benign 16-33438853-C-T74.34e-6-6.888Likely Benign0.120Likely BenignLikely Benign0.382Likely Benign0.54Ambiguous0.0-0.05Likely Benign0.25Likely Benign0.41Likely Benign-1.97Neutral0.977Probably Damaging0.469Possibly Damaging-1.26Pathogenic0.24Tolerated3.3735002.428.05220.3-45.10.00.0-0.70.1XPotentially BenignAla537 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala537 is on the surface and does not form any interactions. In the variant simulations, the iso-propyl side chain of Val537 is also on the surface, similar to Ala537 in the WT, causing no negative structural effects.
c.1651C>AL551M
(3D Viewer)
GAPUncertain 16-33438894-C-A74.34e-6-9.937Likely Pathogenic0.480AmbiguousLikely Benign0.544Likely Pathogenic-0.07Likely Benign0.10.13Likely Benign0.03Likely Benign0.71Ambiguous-0.56Neutral1.000Probably Damaging1.000Probably Damaging-1.48Pathogenic0.06Tolerated3.373542-1.918.03246.5-18.60.00.00.30.0XPotentially BenignL551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the thioether side chain of Met551 can maintain similar hydrophobic interactions as Leu551 in the WT, thus causing no negative effect on the protein structure during the simulations.
c.2765G>AR922QLikely BenignBenign 16-33443317-G-A74.34e-6-3.295Likely Benign0.189Likely BenignLikely Benign0.085Likely Benign-0.27Neutral0.992Probably Damaging0.736Possibly Damaging2.57Benign0.20Tolerated3.775111.0-28.06
c.3184G>AG1062RLikely BenignConflicting 26-33443736-G-A74.35e-6-6.933Likely Benign0.353AmbiguousLikely Benign0.403Likely Benign-0.34Neutral0.797Possibly Damaging0.139Benign4.10Benign0.01Affected4.322-3-2-4.199.14
c.92G>AR31QLikely BenignUncertain 16-33423501-G-A74.34e-6-4.434Likely Benign0.136Likely BenignLikely Benign0.051Likely Benign-0.92Neutral0.829Possibly Damaging0.614Possibly Damaging4.01Benign0.00Affected4.321111.0-28.06
c.113C>TP38LLikely BenignConflicting 46-33423522-C-T84.96e-6-2.469Likely Benign0.197Likely BenignLikely Benign0.141Likely Benign-2.56Deleterious0.983Probably Damaging0.931Probably Damaging4.02Benign0.00Affected4.321-3-35.416.04
c.1136C>TS379L
(3D Viewer)
Likely BenignC2Benign 16-33438041-C-T84.05e-5-5.641Likely Benign0.173Likely BenignLikely Benign0.469Likely Benign0.39Likely Benign0.23.38Destabilizing1.89Ambiguous-0.52Ambiguous-0.85Neutral0.015Benign0.002Benign3.83Benign0.04Affected4.3211-3-24.626.08251.9-48.10.61.10.00.5UncertainSer379 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Leu379 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn.
c.1193C>TP398L
(3D Viewer)
C2Uncertain 16-33438098-C-T84.96e-6-7.518In-Between0.547AmbiguousLikely Benign0.599Likely Pathogenic1.48Ambiguous0.2-0.54Ambiguous0.47Likely Benign0.62Ambiguous-7.10Deleterious0.961Probably Damaging0.256Benign5.72Benign0.01Affected3.4016-3-35.416.04245.8-68.6-0.10.0-0.30.2XPotentially PathogenicPro398 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. Although the residue swap does not influence the nearby secondary structure elements, proline is often found at the ends of β sheets due to its disfavored status during folding.Additionally, the Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone. Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Leu398 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn.
c.2095G>AV699M
(3D Viewer)
GAPUncertain 26-33441354-G-A84.96e-6-8.869Likely Pathogenic0.484AmbiguousLikely Benign0.276Likely Benign-0.58Ambiguous0.10.29Likely Benign-0.15Likely Benign0.96Ambiguous-2.18Neutral0.994Probably Damaging0.806Possibly Damaging3.37Benign0.03Affected3.471021-2.332.06257.8-47.20.00.00.90.1XPotentially BenignThe isopropyl side chain of Val699, located on an α-helix (res. Leu685-Gln702), packs against hydrophobic residues (e.g., Leu703, Leu696, Leu435, Leu439) in the inter-helix space. In the variant simulations, the thioether side chain of Met699 has similar physicochemical properties to Val699 in the WT, and thus, it is able to maintain similar interactions. Consequently, the mutation causes no apparent changes in the structure.
c.2206C>TR736CConflicting 36-33441671-C-T84.96e-6-7.113In-Between0.120Likely BenignLikely Benign0.190Likely Benign-2.06Neutral0.999Probably Damaging0.825Possibly Damaging2.48Pathogenic0.00Affected4.073-4-37.0-53.05
c.1742G>AR581Q
(3D Viewer)
Likely PathogenicGAPBenign 16-33440794-G-A84.96e-6-7.584In-Between0.673Likely PathogenicLikely Benign0.481Likely Benign1.31Ambiguous0.1-0.42Likely Benign0.45Likely Benign0.88Ambiguous-2.77Deleterious1.000Probably Damaging0.995Probably Damaging-1.21Pathogenic0.11Tolerated3.3734111.0-28.06239.653.5-0.20.2-0.40.1XPotentially PathogenicArg581 is located on a short α-α loop between two α helices (res. Arg563-Glu578 and res. Glu582-Ser604). In the WT simulations, the guanidinium group of Arg581 forms salt bridges with the carboxylate groups of Asp583 within the same helix, as well as with Glu478 and/or Glu480 on a slightly α-helical loop (res. Glu478-Thr488) preceding another α helix (res. Ala461-Phe476).In the variant simulations, the neutral carboxamide group of the Gln581 side chain cannot form any of these salt bridges. Instead, it packs hydrophobically against Met477 and Ile587 or forms hydrogen bonds sporadically with nearby residues (e.g., Asp583, Arg587). Thus, although no drastic changes are observed in the variant simulations, the residue swap could weaken the tertiary structure assembly.
c.2714G>AR905HLikely BenignUncertain 16-33443266-G-A84.96e-6-4.182Likely Benign0.457AmbiguousLikely Benign0.192Likely Benign-1.11Neutral1.000Probably Damaging0.991Probably Damaging2.59Benign0.09Tolerated3.775201.3-19.05
c.2888A>GH963RLikely BenignUncertain 16-33443440-A-G84.96e-6-8.952Likely Pathogenic0.169Likely BenignLikely Benign0.081Likely Benign-1.28Neutral0.001Benign0.003Benign4.15Benign0.24Tolerated3.77520-1.319.05
c.2971G>AG991RLikely BenignConflicting 36-33443523-G-A84.96e-6-3.934Likely Benign0.411AmbiguousLikely Benign0.102Likely Benign-1.20Neutral0.984Probably Damaging0.772Possibly Damaging4.11Benign0.01Affected4.322-3-2-4.199.14
c.962G>AR321H
(3D Viewer)
C2Uncertain 16-33437867-G-A84.96e-6-8.751Likely Pathogenic0.136Likely BenignLikely Benign0.323Likely Benign0.48Likely Benign0.1-0.36Likely Benign0.06Likely Benign0.59Ambiguous-1.43Neutral1.000Probably Damaging0.998Probably Damaging1.92Pathogenic0.25Tolerated3.3823201.3-19.05218.586.91.10.00.30.0XPotentially BenignThe guanidinium group of Arg321, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), faces outward without forming any stable interactions in the WT simulations. Similarly, in the variant simulations, the imidazole ring of His321 also points outward without making any stable intra-protein interactions. Thus, the residue swap does not seem to cause adverse effects on the protein structure based on the simulations. However, β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.
c.1040C>AT347N
(3D Viewer)
Likely BenignC2Uncertain 16-33437945-C-A95.58e-6-5.545Likely Benign0.165Likely BenignLikely Benign0.059Likely Benign0.41Likely Benign0.10.46Likely Benign0.44Likely Benign-0.06Likely Benign1.96Neutral0.001Benign0.001Benign1.67Pathogenic0.60Tolerated3.372500-2.813.00
c.1067G>AR356H
(3D Viewer)
Likely PathogenicC2Likely Benign 16-33437972-G-A95.66e-6-11.453Likely Pathogenic0.614Likely PathogenicLikely Benign0.314Likely Benign0.59Ambiguous0.1-0.27Likely Benign0.16Likely Benign1.17Destabilizing-4.43Deleterious0.999Probably Damaging0.987Probably Damaging1.70Pathogenic0.01Affected3.3922021.3-19.05
c.1154C>TS385L
(3D Viewer)
Likely BenignC2Uncertain 26-33438059-C-T94.60e-5-6.018Likely Benign0.167Likely BenignLikely Benign0.304Likely Benign0.16Likely Benign0.10.08Likely Benign0.12Likely Benign-0.26Likely Benign-0.68Neutral0.829Possibly Damaging0.706Possibly Damaging4.63Benign0.01Affected4.323-3-24.626.08244.6-50.10.00.6-0.10.1UncertainSer385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Leu385 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn.
c.1453C>TR485C
(3D Viewer)
Likely PathogenicGAPUncertain 26-33438485-C-T95.58e-6-14.294Likely Pathogenic0.976Likely PathogenicLikely Pathogenic0.597Likely Pathogenic1.00Ambiguous0.10.26Likely Benign0.63Ambiguous0.44Likely Benign-7.96Deleterious1.000Probably Damaging1.000Probably Damaging1.90Pathogenic0.00Affected3.3735-4-37.0-53.05225.599.6-0.10.0-0.30.2XUncertainThe guanidinium group of Arg485 is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. The side chain of Arg485 acts as the “arginine finger” of SynGAP, playing a crucial role in Ras-GTPase activation. Consequently, the residue swap inhibits the conversion of GTP to GDP at the enzyme’s active site. Although no negative effects on the protein structure are observed during the simulations, no definite conclusions can be drawn due to the critical role of Arg485 in GTPase activation.
c.2668C>TR890CBenign 16-33443220-C-T95.58e-6-5.786Likely Benign0.402AmbiguousLikely Benign0.200Likely Benign-3.38Deleterious1.000Probably Damaging0.971Probably Damaging3.94Benign0.04Affected4.324-4-37.0-53.05
c.2743G>AG915SLikely BenignBenign 16-33443295-G-A95.58e-6-3.557Likely Benign0.083Likely BenignLikely Benign0.050Likely Benign-0.88Neutral0.801Possibly Damaging0.201Benign2.73Benign0.31Tolerated3.77510-0.430.03
c.3572G>AR1191QLikely BenignCoiled-coilUncertain 26-33444607-G-A95.58e-6-1.069Likely Benign0.943Likely PathogenicAmbiguous0.343Likely Benign-1.41Neutral0.998Probably Damaging0.992Probably Damaging2.68Benign0.08Tolerated3.824111.0-28.06
c.371C>TA124VLikely BenignConflicting 26-33432236-C-T95.58e-6-4.259Likely Benign0.138Likely BenignLikely Benign0.073Likely Benign-1.52Neutral0.173Benign0.009Benign4.07Benign0.03Affected3.615002.428.05
c.514C>TR172WLikely PathogenicUncertain 26-33435156-C-T95.58e-6-10.258Likely Pathogenic0.878Likely PathogenicAmbiguous0.228Likely Benign-3.61Deleterious0.997Probably Damaging0.803Possibly Damaging3.95Benign0.00Affected3.6152-33.630.03
c.70G>AV24ILikely BenignUncertain 16-33423479-G-A95.58e-6-3.701Likely Benign0.137Likely BenignLikely Benign0.069Likely Benign-0.25Neutral0.043Benign0.031Benign3.96Benign0.00Affected4.321340.314.03
c.961C>TR321C
(3D Viewer)
Likely PathogenicC2Conflicting 26-33437866-C-T95.58e-6-10.025Likely Pathogenic0.387AmbiguousLikely Benign0.495Likely Benign0.57Ambiguous0.10.56Ambiguous0.57Ambiguous0.18Likely Benign-4.59Deleterious1.000Probably Damaging0.998Probably Damaging1.89Pathogenic0.01Affected3.3823-3-47.0-53.05
c.1286G>AR429Q
(3D Viewer)
Likely BenignGAPUncertain 26-33438191-G-A106.20e-6-8.227Likely Pathogenic0.143Likely BenignLikely Benign0.156Likely Benign0.45Likely Benign0.10.36Likely Benign0.41Likely Benign0.98Ambiguous-1.25Neutral1.000Probably Damaging0.979Probably Damaging3.47Benign0.58Tolerated3.3825111.0-28.06235.859.50.00.0-0.30.4XPotentially PathogenicThe guanidinium group of the Arg429 side chain, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or an H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, Gln429 cannot form ionic interactions with the acidic residues; however, the carboxamide group can form multiple H-bonds. The H-bonding coordination of the Asn429 side chain varied between the replica simulations. In one simulation, three H-bonds were formed simultaneously with the Asp467 side chain, the backbone carbonyl group of Asn426, and the amide group of Met430 at the end of the same α helix. The residue swap could affect the tertiary structure assembly during folding due to weaker bond formation, but no large-scale negative effects were seen during the simulations.
c.1904A>GN635S
(3D Viewer)
GAPConflicting 46-33440956-A-G106.20e-6-9.002Likely Pathogenic0.101Likely BenignLikely Benign0.104Likely Benign0.80Ambiguous0.10.67Ambiguous0.74Ambiguous0.95Ambiguous-4.45Deleterious0.261Benign0.044Benign3.06Benign0.05Affected3.3734112.7-27.03196.030.90.10.0-0.30.2XUncertainIn the WT simulations, the carboxamide side chain of Asn635, located on the outer surface of an α helix (res. Glu617-Asn635), forms hydrogen bonds with Gln631 on the same α helix and with the hydroxyl side chain of Ser590 on an opposing α helix (res. Glu582-Met603).In the variant simulations, the side chain of Ser635 is shorter than asparagine and thus prefers to hydrogen bond with the carbonyl group of Gln631 on the same helix and, to a lesser extent, with Ser590 compared to Asn635 in the WT. Ser635 forms hydrogen bonds with the backbone atoms of the same helix, which may destabilize the helix, although this is not clearly evident in the simulations. The weakening of the hydrogen bond between Ser635 and Ser590 in the variant may also weaken the tertiary structure assembly between the helices.Additionally, Asn635 is at the GTPase interface. However, the implication of the residue swap on the complex formation with the GTPase cannot be investigated using solvent-only simulations.
c.1997A>GE666G
(3D Viewer)
Likely PathogenicGAPLikely Benign 16-33441256-A-G106.20e-6-12.261Likely Pathogenic0.911Likely PathogenicAmbiguous0.522Likely Pathogenic1.57Ambiguous0.11.46Ambiguous1.52Ambiguous0.93Ambiguous-6.25Deleterious1.000Probably Damaging0.970Probably Damaging3.37Benign0.02Affected3.38280-23.1-72.06173.998.50.00.0-0.70.0XPotentially PathogenicIn the WT simulations, the carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669. In the variant simulations, the carbonyl group of Gly666 occasionally forms hydrogen bonds with Lys566 and Asn669. However, Gly666 lacks a side chain and thus cannot maintain as well-coordinated a hydrogen-bond network as Glu666 in the WT, which may affect the tertiary structure assembly.
c.3055C>TR1019CLikely PathogenicConflicting 26-33443607-C-T106.19e-6-7.386In-Between0.646Likely PathogenicLikely Benign0.168Likely Benign-4.00Deleterious0.999Probably Damaging0.880Possibly Damaging2.36Pathogenic0.00Affected3.775-4-37.0-53.0510.1016/j.ajhg.2020.11.011
c.3961C>TP1321SLikely BenignUncertain 26-33451835-C-T106.46e-6-4.897Likely Benign0.077Likely BenignLikely Benign0.049Likely Benign0.68Neutral0.028Benign0.004Benign4.27Benign0.71Tolerated3.7751-10.8-10.0410.1016/j.ajhg.2020.11.011
c.50C>TS17FLikely BenignUncertain 16-33420314-C-T106.49e-6-3.888Likely Benign0.637Likely PathogenicLikely Benign0.048Likely Benign-0.99Neutral0.486Possibly Damaging0.032Benign3.99Benign0.00Affected4.321-2-33.660.10
c.773G>AR258H
(3D Viewer)
C2Benign/Likely benign 36-33437678-G-A106.20e-6-10.533Likely Pathogenic0.525AmbiguousLikely Benign0.830Likely Pathogenic1.60Ambiguous0.61.00Ambiguous1.30Ambiguous1.47Destabilizing-4.06Deleterious1.000Probably Damaging0.991Probably Damaging5.77Benign0.01Affected3.3915201.3-19.05212.581.80.10.0-0.50.2XPotentially PathogenicThe guanidinium group of Arg258, located at the end of an α-β loop connecting the PH domain to the C2 domain (res. Lys251-Arg258), forms hydrogen bonds with the carboxamide groups of Asn727 and Asn729 side chains, as well as with the backbone carbonyl groups of Ala724, Leu725, and Asn727 in the WT simulations. Although the imidazole group of His258 can act as a hydrogen bond donor/acceptor, the swapped residue is unable to maintain an equally well-coordinated hydrogen bond network for linking the C2 and GAP domains in the variant simulations.
c.896G>AR299H
(3D Viewer)
C2Conflicting 26-33437801-G-A106.20e-6-7.731In-Between0.388AmbiguousLikely Benign0.238Likely Benign3.97Destabilizing1.00.94Ambiguous2.46Destabilizing1.41Destabilizing-3.35Deleterious1.000Probably Damaging0.998Probably Damaging1.69Pathogenic0.02Affected3.3919201.3-19.05211.272.5-0.10.2-0.20.3XPotentially PathogenicThe guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the imidazole ring of His299 (epsilon protonated state) hydrogen bonds with the carbonyl group of Asp304 and the hydroxyl group of Ser300. However, it does not form as many or as strong interactions as arginine, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.Additionally, His299 prefers to hydrophobically interact with other hydrophobic residues inside the C2 domain core (e.g., Val306, Leu274), which destabilizes the C2 domain. Indeed, the β strand partially unfolds during the second simulation. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association.
c.2282G>AR761QLikely BenignUncertain 16-33441747-G-A116.81e-6-4.187Likely Benign0.202Likely BenignLikely Benign0.191Likely Benign-0.63Neutral0.996Probably Damaging0.878Possibly Damaging2.75Benign0.40Tolerated3.995111.0-28.06
c.2324G>AR775QLikely BenignConflicting 36-33442482-G-A111.41e-5-4.476Likely Benign0.229Likely BenignLikely Benign0.085Likely Benign-0.63Neutral0.969Probably Damaging0.863Possibly Damaging4.17Benign0.16Tolerated3.646111.0-28.0610.1016/j.ajhg.2020.11.011
c.3304G>AA1102TLikely BenignUncertain 16-33443856-G-A117.17e-6-3.540Likely Benign0.070Likely BenignLikely Benign0.044Likely Benign-0.30Neutral0.001Benign0.001Benign2.32Pathogenic0.95Tolerated3.77510-2.530.03
c.3376G>TG1126CLikely BenignUncertain 16-33443928-G-T117.35e-6-9.389Likely Pathogenic0.113Likely BenignLikely Benign0.449Likely Benign-1.40Neutral0.005Benign0.005Benign4.74Benign0.02Affected3.775-3-32.946.09
c.3920C>TP1307LLikely BenignBenign 16-33451794-C-T116.82e-6-4.044Likely Benign0.144Likely BenignLikely Benign0.292Likely Benign-1.49Neutral0.779Possibly Damaging0.220Benign2.82Benign0.04Affected3.775-3-35.416.04
c.3116T>CI1039TLikely BenignUncertain 16-33443668-T-C127.43e-6-2.465Likely Benign0.645Likely PathogenicLikely Benign0.193Likely Benign0.45Neutral0.004Benign0.008Benign2.75Benign0.10Tolerated3.775-10-5.2-12.05
c.3410A>CH1137PLikely BenignBenign 16-33444445-A-C127.44e-6-2.098Likely Benign0.054Likely BenignLikely Benign0.419Likely Benign-1.93Neutral0.925Possibly Damaging0.703Possibly Damaging5.29Benign0.00Affected4.324-201.6-40.02
c.4013G>AR1338QLikely BenignConflicting 36-33451887-G-A128.40e-6-3.494Likely Benign0.317Likely BenignLikely Benign0.076Likely Benign-1.87Neutral0.896Possibly Damaging0.194Benign3.81Benign0.02Affected3.775111.0-28.06
c.1454G>AR485H
(3D Viewer)
Likely PathogenicGAPLikely Benign 16-33438486-G-A138.05e-6-13.628Likely Pathogenic0.948Likely PathogenicAmbiguous0.618Likely Pathogenic0.77Ambiguous0.10.12Likely Benign0.45Likely Benign1.13Destabilizing-4.97Deleterious1.000Probably Damaging0.998Probably Damaging1.93Pathogenic0.00Affected3.3735021.3-19.05
c.2830G>AG944SLikely BenignBenign 16-33443382-G-A138.05e-6-5.303Likely Benign0.082Likely BenignLikely Benign0.223Likely Benign-0.75Neutral0.007Benign0.004Benign3.77Benign0.00Affected4.32410-0.430.03
c.2837G>AG946ELikely BenignBenign 36-33443389-G-A138.05e-6-8.793Likely Pathogenic0.257Likely BenignLikely Benign0.341Likely Benign-0.51Neutral0.818Possibly Damaging0.355Benign4.58Benign0.00Affected4.3240-2-3.172.06
c.3638A>GN1213SLikely BenignCoiled-coilBenign 16-33446630-A-G138.05e-6-4.086Likely Benign0.081Likely BenignLikely Benign0.094Likely Benign-0.56Neutral0.906Possibly Damaging0.551Possibly Damaging2.82Benign0.68Tolerated3.775112.7-27.0310.1016/j.ajhg.2020.11.011
c.407G>AR136QBenign 16-33432704-G-A139.17e-6-11.146Likely Pathogenic0.950Likely PathogenicAmbiguous0.190Likely Benign-2.26Neutral0.957Probably Damaging0.342Benign3.52Benign0.01Affected3.615111.0-28.06
c.913A>GT305A
(3D Viewer)
Likely BenignC2Conflicting 26-33437818-A-G138.05e-6-4.307Likely Benign0.078Likely BenignLikely Benign0.144Likely Benign1.30Ambiguous0.61.55Ambiguous1.43Ambiguous0.77Ambiguous-2.10Neutral0.939Possibly Damaging0.645Possibly Damaging1.76Pathogenic0.12Tolerated3.4020102.5-30.03177.943.5-0.20.10.40.0UncertainThe hydroxyl group of Thr305, located at the beginning of an anti-parallel β strand (res. Thr305-Asn315), hydrogen bonds with the carboxylate groups of Glu270 and Asp304 in the anti-parallel β strand and the adjacent β hairpin loop, respectively. In the variant simulations, the methyl group of the Ala305 side chain cannot hydrogen bond with either of the acidic residues, which could weaken the integrity of the tertiary structure and the β hairpin loop. Indeed, the guanidinium group of Arg299 does not acquire its central hairpin loop position due to the residue swap.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel.
c.1604G>CS535T
(3D Viewer)
Likely BenignGAPBenign 16-33438847-G-C148.67e-6-3.886Likely Benign0.069Likely BenignLikely Benign0.177Likely Benign0.45Likely Benign0.1-0.27Likely Benign0.09Likely Benign0.17Likely Benign-0.81Neutral0.000Benign0.001Benign-1.25Pathogenic0.25Tolerated3.3735110.114.03201.3-17.3-0.10.7-0.20.1XPotentially BenignSer535 is located near the terminal end of an α-helix (res. Ala533-Val560) close to the membrane interface. In the WT simulations, the hydroxyl side chain of Ser535 forms hydrogen bonds with nearby residues (e.g., His539, Glu538) without any specific interactions. These hydrogen bonds disrupt the structure of the terminal end of the α-helix (Ala533-Ser535), causing it to weaken or unfold during the WT simulations. In the variant simulations, Thr535, a hydrophilic residue with a hydroxyl group of almost the same size as Ser, interacts more frequently with the preceding loop residues (e.g., Thr532, Cys531) due to its longer side chain. Regardless, the residue swap is tolerated in the simulations with no negative effects. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations.10.1016/j.ajhg.2020.11.011
c.1768A>GS590G
(3D Viewer)
Likely PathogenicGAPConflicting 26-33440820-A-G148.67e-6-14.277Likely Pathogenic0.574Likely PathogenicLikely Benign0.379Likely Benign0.67Ambiguous0.11.28Ambiguous0.98Ambiguous0.71Ambiguous-3.92Deleterious1.000Probably Damaging0.922Probably Damaging3.42Benign0.06Tolerated3.3735100.4-30.03186.749.40.00.00.10.0XPotentially PathogenicIn the WT simulations, the hydroxyl group of Ser590, located on an α helix (res. Glu582-Met603), forms hydrogen bonds with the backbone carbonyl of Ala634 and/or the carboxamide group of the Asn635 side chain at the end of the opposing α helix (res. Thr619-Ala634).The residue swap could weaken the integrity of the α helix, as glycine is known as an “α helix breaker.” However, no discernible difference was observed between the WT and variant simulations in this regard. Importantly, Gly590 cannot form hydrogen bonds with the opposing helix in the same way that serine can, which could weaken the tertiary structure assembly between the two helices.
c.2699C>TT900MLikely BenignConflicting 26-33443251-C-T148.68e-6-3.852Likely Benign0.176Likely BenignLikely Benign0.015Likely Benign-0.81Neutral0.060Benign0.016Benign2.79Benign0.08Tolerated4.324-1-12.630.09
c.3194C>TP1065LLikely Benign 16-33443746-C-T148.71e-6-5.085Likely Benign0.089Likely BenignLikely Benign0.068Likely Benign-2.94Deleterious0.950Possibly Damaging0.419Benign2.01Pathogenic0.00Affected4.322-3-35.416.04
c.3197C>TP1066LLikely BenignLikely Benign 16-33443749-C-T148.71e-6-5.478Likely Benign0.092Likely BenignLikely Benign0.173Likely Benign-3.68Deleterious0.996Probably Damaging0.903Possibly Damaging2.72Benign0.00Affected4.322-3-35.416.04
c.815G>AR272Q
(3D Viewer)
C2Uncertain 26-33437720-G-A148.67e-6-9.559Likely Pathogenic0.286Likely BenignLikely Benign0.321Likely Benign0.73Ambiguous0.10.15Likely Benign0.44Likely Benign1.00Destabilizing-1.81Neutral0.999Probably Damaging0.994Probably Damaging1.88Pathogenic0.03Affected3.3819111.0-28.06255.752.90.00.0-0.20.1XUncertainThe guanidinium group of Arg272, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), is stably maintained in an upright and outward position via stacking with the indole ring of the Trp362 side chain in another β strand (res. Thr359-Pro364). In the WT simulations, Arg272 forms hydrogen bonds with the glycine-rich Ω loop residues (res. Val365-Pro398, e.g., Gly380) and creates a salt bridge with the carboxylate group of the Asp304 side chain.In the variant simulations, the carboxamide group of the Gln272 side chain does not stack with the indole ring of Trp362 as stably as the guanidinium group of Arg272 in the WT. Consequently, the Gln272 side chain is freer to interact with the loop residues than Arg272, potentially negatively affecting the dynamic SynGAP-membrane association. Additionally, Arg272 faces the RasGTPase interface, so the residue swap could impact the SynGAP-Ras complex formation and GTPase activation.
c.1108G>AG370S
(3D Viewer)
Likely BenignC2Uncertain 16-33438013-G-A159.31e-6-3.533Likely Benign0.081Likely BenignLikely Benign0.282Likely Benign2.83Destabilizing2.01.05Ambiguous1.94Ambiguous-0.02Likely Benign0.47Neutral0.000Benign0.000Benign1.33Pathogenic0.77Tolerated3.421910-0.430.03196.6-49.60.92.2-0.10.4UncertainGly370 is located in the Gly-rich Ω loop (res. Pro364- Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because, the Ω loop is assumed to be directly interacting with the membrane, it is only seen to move arbitrarily throughout the WT solvent simulations. The Ω loop is potentially playing a crucial loop in the SynGAP-membrane complex association, stability and dynamics, regardless, this aspect cannot be addressed through the solvent simulations only. The Ω-loops are known to have a major role in protein functions that requires flexibility and thus, they are rich in glycines, prolines and to a lesser extent, hydrophilic residues to ensure maximum flexibility. Thus, Ser370 in the variant is potentially tolerated in the Ω loop. However, since the effect on the Gly-rich Ω loop dynamics can only be well-studied through the SynGAP-membrane complex, no definite conclusions can be withdrawn.
c.1678G>AV560M
(3D Viewer)
GAPUncertain 26-33440730-G-A159.50e-6-9.598Likely Pathogenic0.517AmbiguousLikely Benign0.520Likely Pathogenic-0.33Likely Benign0.10.88Ambiguous0.28Likely Benign0.72Ambiguous-2.42Neutral0.999Probably Damaging0.863Possibly Damaging-1.25Pathogenic0.14Tolerated3.373521-2.332.06234.9-52.60.00.0-0.10.1XPotentially BenignVal560 is located on the surface at the end of an α-helix (res. Ala533-Val560). The iso-propyl group of Val560 favorably packs against Asp508 of the opposing α-helix (res. Gln503-Glu519). However, in the variant simulations, the bulkier thioether side chain of Met560 does not form equally favorable inter-helix interactions. Regardless, no negative structural effects are observed during the simulations.
c.1787G>AR596H
(3D Viewer)
Likely PathogenicGAPLikely Benign 16-33440839-G-A159.29e-6-11.128Likely Pathogenic0.950Likely PathogenicAmbiguous0.717Likely Pathogenic3.00Destabilizing0.90.43Likely Benign1.72Ambiguous1.35Destabilizing-4.97Deleterious1.000Probably Damaging0.999Probably Damaging2.43Pathogenic0.00Affected3.3735201.3-19.05223.580.5-0.10.0-0.10.3XXPotentially PathogenicThe guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the imidazole ring of His596 can form hydrogen bonds with the same residues as arginine; however, these interactions are not as coordinated or strong in comparison. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation.
c.2713C>TR905CConflicting 26-33443265-C-T159.31e-6-5.578Likely Benign0.723Likely PathogenicLikely Benign0.194Likely Benign-3.14Deleterious1.000Probably Damaging0.980Probably Damaging2.57Benign0.01Affected3.775-4-37.0-53.05
c.335G>CG112ALikely BenignUncertain 16-33432200-G-C159.30e-6-2.456Likely Benign0.119Likely BenignLikely Benign0.114Likely Benign-2.34Neutral0.231Benign0.054Benign4.07Benign0.00Affected3.615102.214.03
c.3902C>GP1301RLikely BenignUncertain 16-33451776-C-G159.30e-6-4.753Likely Benign0.162Likely BenignLikely Benign0.076Likely Benign-1.13Neutral0.077Benign0.059Benign2.81Benign0.10Tolerated3.7750-2-2.959.07
c.74G>AR25QLikely BenignUncertain 16-33423483-G-A159.29e-6-4.126Likely Benign0.212Likely BenignLikely Benign0.038Likely Benign-0.70Neutral0.829Possibly Damaging0.614Possibly Damaging4.01Benign0.00Affected4.321111.0-28.06
c.1312G>AA438T
(3D Viewer)
Likely BenignGAPConflicting 36-33438217-G-A169.91e-6-5.339Likely Benign0.085Likely BenignLikely Benign0.021Likely Benign0.21Likely Benign0.0-0.07Likely Benign0.07Likely Benign0.36Likely Benign-0.81Neutral0.300Benign0.011Benign4.18Benign0.14Tolerated3.382610-2.530.03214.2-42.7-0.30.1-0.40.1XPotentially BenignThe methyl group of Ala438, located in a four-residue loop connecting two α helices (res. Asn440-Thr458 and Pro413-Glu436), packs against hydrophobic residues from a nearby α helix or loop residues (e.g., Leu703, Val699). In the variant simulations, the methyl group of Thr438 is able to establish similar hydrophobic packing. Moreover, the hydroxyl group also H-bonds with nearby residues, such as the carbonyl group of the neighboring loop residue Pro437. Accordingly, the residue swap does not generate an apparent negative effect on the protein structure based on the simulations.
c.1441C>TH481Y
(3D Viewer)
Likely PathogenicGAPLikely Benign 16-33438473-C-T169.91e-6-10.910Likely Pathogenic0.565Likely PathogenicLikely Benign0.256Likely Benign-0.53Ambiguous0.1-0.46Likely Benign-0.50Ambiguous0.20Likely Benign-3.32Deleterious0.988Probably Damaging0.979Probably Damaging3.40Benign0.59Tolerated3.3733021.926.03256.5-44.40.00.00.20.2XXUncertainThe imidazole ring of the His481 side chain is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. In the WT simulations, His481 alternately stacks against Arg485, Arg587, and Glu480 without a definite role. In the variant simulations, Tyr481 also alternately stacks with nearby arginine residues, including Arg485, Arg587, and Arg479. The interaction between Tyr481 and Arg479 affects the α-α loop, causing it to fold into a distorted helical structure, an effect that might be more pronounced during protein folding. Finally, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations.
c.2339C>GS780CLikely BenignUncertain 46-33442891-C-G169.94e-6-7.603In-Between0.278Likely BenignLikely Benign0.078Likely Benign-1.41Neutral0.065Benign0.043Benign2.59Benign0.10Tolerated3.646-103.316.06
c.3379G>CG1127RLikely BenignConflicting 26-33443931-G-C161.07e-5-5.949Likely Benign0.629Likely PathogenicLikely Benign0.341Likely Benign-0.87Neutral0.001Benign0.001Benign4.86Benign0.12Tolerated4.324-2-3-4.199.14
c.2359C>AP787TLikely PathogenicSH3-binding motifLikely Benign 16-33442911-C-A171.05e-5-4.813Likely Benign0.603Likely PathogenicLikely Benign0.258Likely Benign-4.40Deleterious1.000Probably Damaging0.999Probably Damaging2.46Pathogenic0.01Affected3.6460-10.93.99
c.3238G>AA1080TLikely BenignConflicting 26-33443790-G-A171.06e-5-3.928Likely Benign0.133Likely BenignLikely Benign0.144Likely Benign-0.19Neutral0.253Benign0.042Benign4.10Benign0.60Tolerated3.77510-2.530.03
c.3929C>TT1310MLikely BenignBenign 16-33451803-C-T171.05e-5-4.822Likely Benign0.117Likely BenignLikely Benign0.069Likely Benign2.19Neutral0.021Benign0.005Benign2.98Benign0.93Tolerated3.775-1-12.630.09
c.1736G>AR579Q
(3D Viewer)
Likely PathogenicGAPUncertain 16-33440788-G-A181.12e-5-9.193Likely Pathogenic0.690Likely PathogenicLikely Benign0.673Likely Pathogenic0.65Ambiguous0.10.70Ambiguous0.68Ambiguous1.13Destabilizing-3.31Deleterious1.000Probably Damaging0.995Probably Damaging-1.34Pathogenic0.06Tolerated3.3734111.0-28.06
c.1771G>AA591T
(3D Viewer)
Likely PathogenicGAPConflicting 36-33440823-G-A181.12e-5-9.572Likely Pathogenic0.704Likely PathogenicLikely Benign0.270Likely Benign1.61Ambiguous0.21.00Ambiguous1.31Ambiguous1.19Destabilizing-3.40Deleterious0.955Possibly Damaging0.209Benign3.48Benign0.01Affected3.373510-2.530.03202.9-43.40.20.00.70.1XPotentially BenignThe methyl group of the Ala591 side chain, located in the middle of an α helix (res. Glu582-Met603), packs against hydrophobic residues (e.g., Ile483, Phe484) of an opposing partially helical loop (res. Phe476-Asn487).In the variant simulations, the hydroxyl group of Thr591 can form hydrogen bonds with the backbone carbonyl of Ile843 in the opposing loop or the backbone carbonyl group of Arg587. These interactions could either reinforce the tertiary assembly or weaken the α helix unity. Additionally, the Thr591 side chain can hydrogen bond with the guanidinium group of the Arg587 side chain, potentially strengthening the α helix unity.Overall, the residue swap does not seem to cause any major negative effects on the protein structure.
c.2657C>TA886VLikely BenignUncertain 16-33443209-C-T181.12e-5-4.478Likely Benign0.078Likely BenignLikely Benign0.061Likely Benign-0.20Neutral0.888Possibly Damaging0.314Benign2.17Pathogenic0.00Affected4.324002.428.05
c.1862G>AR621Q
(3D Viewer)
Likely PathogenicGAPLikely Benign 16-33440914-G-A191.18e-5-14.682Likely Pathogenic0.910Likely PathogenicAmbiguous0.621Likely Pathogenic0.81Ambiguous0.11.13Ambiguous0.97Ambiguous1.35Destabilizing-3.98Deleterious1.000Probably Damaging0.997Probably Damaging2.82Benign0.01Affected3.3735111.0-28.06243.754.30.00.0-0.40.2XXPotentially PathogenicThe guanidinium group of Arg621, located in an α helix (res. Glu617-Asn635), forms a salt bridge with Glu525 in a nearby loop and stacks with Leu635. In the variant simulations, the carboxamide side chain of Gln621, which can act as both a hydrogen bond acceptor and donor, also stacks with Leu635 but can only sporadically hydrogen bond with Glu525.Accordingly, the residue swap could affect the tertiary structure integrity by disrupting the salt bridge formation. Additionally, due to its location at the GAP-Ras interface, the residue swap could impact the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations.
c.2015C>TT672M
(3D Viewer)
GAPConflicting 26-33441274-C-T191.18e-5-9.472Likely Pathogenic0.174Likely BenignLikely Benign0.127Likely Benign0.31Likely Benign0.41.52Ambiguous0.92Ambiguous0.41Likely Benign-4.34Deleterious0.993Probably Damaging0.520Possibly Damaging3.39Benign0.00Affected3.4025-1-12.630.09231.9-52.91.10.10.50.0XXPotentially PathogenicThe hydroxyl group of Thr672, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop itself, such as Lys566, Glu666, and Asn669. Met672 can only form a hydrogen bond with the amino group of the Lys566 side chain via its backbone carbonyl group. Nevertheless, the Lys566-Glu666 salt bridge forms intermittently. This is possible because Asn669 keeps the carboxylate group of Glu666 in the vicinity through hydrogen bonding, and the hydrophobic side chain of Met stays mostly rotated away from the salt bridge. Consequently, no drastic disruption of the hydrogen-bond network that keeps the loop close to the helices occurs in the variant simulations.
c.2669G>AR890HLikely BenignBenign 16-33443221-G-A191.18e-5-3.600Likely Benign0.198Likely BenignLikely Benign0.056Likely Benign-1.29Neutral0.254Benign0.134Benign3.97Benign0.15Tolerated4.324201.3-19.05
c.29G>AR10QLikely BenignUncertain 26-33420293-G-A201.30e-5-4.438Likely Benign0.185Likely BenignLikely Benign0.084Likely Benign0.03Neutral0.121Benign0.004Benign4.17Benign0.00Affected4.321111.0-28.06
c.3995C>TT1332MLikely Benign 16-33451869-C-T201.86e-5-4.107Likely Benign0.948Likely PathogenicAmbiguous0.252Likely Benign-3.63Deleterious1.000Probably Damaging0.991Probably Damaging2.95Benign0.00Affected3.775-1-12.630.09
c.603T>GD201E
(3D Viewer)
Likely BenignPHConflicting 26-33435245-T-G201.24e-5-2.640Likely Benign0.406AmbiguousLikely Benign0.165Likely Benign0.42Likely Benign0.21.99Ambiguous1.21Ambiguous0.23Likely Benign-0.69Neutral0.633Possibly Damaging0.108Benign4.30Benign1.00Tolerated3.469320.014.03258.7-24.80.90.1-0.30.2XUncertainAsp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations.
c.1025A>GY342C
(3D Viewer)
Likely PathogenicC2Benign/Likely benign 26-33437930-A-G211.30e-5-7.596In-Between0.682Likely PathogenicLikely Benign0.404Likely Benign2.48Destabilizing0.12.73Destabilizing2.61Destabilizing0.92Ambiguous-6.67Deleterious1.000Probably Damaging0.999Probably Damaging1.72Pathogenic0.02Affected3.37250-23.8-60.04242.462.80.10.0-0.10.2Potentially PathogenicThe phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. This phenol ring contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Cys342 side chain cannot participate in the stack formation. Instead, its thiol group forms a hydrogen bond with the backbone carbonyl group of Leu327. Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association; however, this phenomenon cannot be addressed using solvent-only simulations. Notably, the thiol group of cysteine is not a particularly strong hydrogen-bonding partner, which could mitigate the negative effects of the residue swap.
c.2578G>AV860ILikely BenignBenign 16-33443130-G-A211.30e-5-4.516Likely Benign0.095Likely BenignLikely Benign0.039Likely Benign-0.42Neutral0.009Benign0.006Benign4.24Benign0.00Affected3.775430.314.03
c.1160G>TG387V
(3D Viewer)
Likely BenignC2Uncertain 16-33438065-G-T221.37e-5-6.199Likely Benign0.153Likely BenignLikely Benign0.390Likely Benign5.13Destabilizing1.86.44Destabilizing5.79Destabilizing-0.33Likely Benign-0.54Neutral0.069Benign0.077Benign1.32Pathogenic0.01Affected4.323-1-34.642.08207.7-68.4-0.70.8-0.50.1UncertainGly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val387 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn.
c.1198G>CV400L
(3D Viewer)
Likely BenignC2Benign 16-33438103-G-C221.36e-5-1.000Likely Benign0.137Likely BenignLikely Benign0.325Likely Benign-0.71Ambiguous0.20.39Likely Benign-0.16Likely Benign-0.29Likely Benign-0.60Neutral0.001Benign0.001Benign5.33Benign0.64Tolerated3.382721-0.414.03251.0-30.10.00.00.70.1XPotentially BenignThe iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations.10.1016/j.ajhg.2020.11.011
c.3397A>GI1133VLikely BenignBenign 16-33443949-A-G221.48e-5-3.362Likely Benign0.067Likely BenignLikely Benign0.180Likely Benign0.06Neutral0.007Benign0.007Benign5.47Benign0.58Tolerated4.32343-0.3-14.0310.1016/j.ajhg.2020.11.011
c.1723C>TR575C
(3D Viewer)
Likely PathogenicGAPConflicting 36-33440775-C-T231.43e-5-11.179Likely Pathogenic0.630Likely PathogenicLikely Benign0.715Likely Pathogenic1.39Ambiguous0.20.50Ambiguous0.95Ambiguous0.73Ambiguous-5.43Deleterious1.000Probably Damaging1.000Probably Damaging-1.30Pathogenic0.02Affected3.3735-4-37.0-53.05227.799.20.00.00.00.1XPotentially PathogenicThe guanidinium group of Arg575, located in an α-helix (res. Arg563-Glu578), forms salt bridges with the carboxylate groups of Asp463 and Asp467, and it also hydrogen bonds with the hydroxyl group of Ser466 on an opposing α-helix (res. Ala461-Phe476) in the WT simulations. In the variant simulations, the thiol group of the Cys575 side chain, which is neither positively charged nor particularly hydrophilic, packs against the hydrophobic Met470 on an opposing α-helix (res. Ala461-Arg475). Additionally, although the thiol group is not an effective hydrogen bonder, the Cys575 side chain rotates to hydrogen bond with the backbone carbonyl group of Ser571 in the same α-helix, which could theoretically lower the helix integrity. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process.
c.163C>AQ55KLikely BenignUncertain 26-33423572-C-A241.49e-5-5.840Likely Benign0.612Likely PathogenicLikely Benign0.085Likely Benign-1.21Neutral0.140Benign0.184Benign3.91Benign0.00Affected4.32111-0.40.04
c.2225G>AR742QLikely BenignUncertain 26-33441690-G-A241.49e-5-4.090Likely Benign0.068Likely BenignLikely Benign0.054Likely Benign-0.19Neutral0.032Benign0.007Benign2.73Benign0.07Tolerated4.322111.0-28.06
c.2444G>AR815HSH3-binding motifLikely Benign 26-33442996-G-A241.49e-5-7.474In-Between0.553AmbiguousLikely Benign0.157Likely Benign-1.81Neutral1.000Probably Damaging0.998Probably Damaging2.61Benign0.02Affected4.324201.3-19.0510.1016/j.ajhg.2020.11.011
c.3370G>AG1124RConflicting 36-33443922-G-A241.60e-5-8.918Likely Pathogenic0.534AmbiguousLikely Benign0.243Likely Benign-0.58Neutral0.002Benign0.002Benign4.81Benign0.01Affected3.775-3-2-4.199.14
c.2111G>AS704N
(3D Viewer)
Likely BenignGAPBenign/Likely benign 36-33441370-G-A271.67e-5-5.917Likely Benign0.421AmbiguousLikely Benign0.058Likely Benign0.48Likely Benign0.1-0.12Likely Benign0.18Likely Benign0.54Ambiguous-0.49Neutral0.771Possibly Damaging0.275Benign3.39Benign0.08Tolerated3.471011-2.727.03233.2-29.1-0.10.0-0.10.1XPotentially BenignSer704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. However, in the variant simulations, the carboxamide side chain of Asn704 achieves more lasting and numerous hydrogen-bonding interactions with the residues at the helix end, such as Glu706, Ala707, and Leu708. Consequently, the residue swap could strengthen the α-helix secondary structure integrity at the helix end, which could have either positive or negative effects on its function.
c.3364G>AG1122SLikely BenignBenign/Likely benign 26-33443916-G-A271.79e-5-4.880Likely Benign0.072Likely BenignLikely Benign0.189Likely Benign-0.08Neutral0.022Benign0.006Benign4.89Benign0.92Tolerated3.77510-0.430.03
c.2669G>CR890PLikely BenignLikely Benign 26-33443221-G-C281.74e-5-1.931Likely Benign0.301Likely BenignLikely Benign0.191Likely Benign-1.21Neutral0.999Probably Damaging0.977Probably Damaging4.02Benign0.28Tolerated4.3240-22.9-59.07
c.2840G>CG947ALikely BenignLikely Benign 16-33443392-G-C281.73e-5-6.511Likely Benign0.080Likely BenignLikely Benign0.156Likely Benign-0.41Neutral0.224Benign0.131Benign4.97Benign0.10Tolerated4.324102.214.03
c.2353C>TR785CLikely PathogenicSH3-binding motifUncertain 16-33442905-C-T291.80e-5-5.887Likely Benign0.662Likely PathogenicLikely Benign0.126Likely Benign-5.06Deleterious0.144Benign0.046Benign2.22Pathogenic0.00Affected3.646-4-37.0-53.05
c.3913A>GT1305ALikely BenignConflicting 46-33451787-A-G301.86e-5-2.692Likely Benign0.055Likely BenignLikely Benign0.069Likely Benign1.74Neutral0.000Benign0.001Benign3.24Benign1.00Tolerated3.775102.5-30.03
c.2900G>AR967QLikely BenignBenign/Likely benign 26-33443452-G-A311.92e-5-3.057Likely Benign0.080Likely BenignLikely Benign0.104Likely Benign-0.01Neutral0.994Probably Damaging0.626Possibly Damaging4.21Benign0.36Tolerated4.322111.0-28.06
c.3308G>AR1103HLikely BenignBenign/Likely benign 36-33443860-G-A312.03e-5-3.622Likely Benign0.156Likely BenignLikely Benign0.116Likely Benign-1.97Neutral0.996Probably Damaging0.733Possibly Damaging2.49Pathogenic0.01Affected3.775201.3-19.05
c.3160G>AG1054SLikely BenignBenign 16-33443712-G-A321.99e-5-5.294Likely Benign0.075Likely BenignLikely Benign0.160Likely Benign0.21Neutral0.121Benign0.013Benign4.04Benign0.63Tolerated3.77510-0.430.03
c.3848C>TP1283LLikely BenignBenign 16-33447896-C-T322.06e-5-3.740Likely Benign0.093Likely BenignLikely Benign0.047Likely Benign-1.04Neutral0.005Benign0.003Benign2.76Benign0.06Tolerated3.775-3-35.416.04
c.3983G>AR1328QLikely BenignUncertain 36-33451857-G-A351.49e-4-2.921Likely Benign0.273Likely BenignLikely Benign0.043Likely Benign-1.02Neutral0.799Possibly Damaging0.098Benign4.12Benign0.03Affected3.775111.0-28.06
c.1480A>GI494V
(3D Viewer)
GAPConflicting 26-33438512-A-G362.23e-5-7.102In-Between0.112Likely BenignLikely Benign0.439Likely Benign1.16Ambiguous0.00.71Ambiguous0.94Ambiguous1.02Destabilizing-0.83Neutral0.278Benign0.179Benign-1.30Pathogenic0.07Tolerated3.373543-0.3-14.03248.629.30.00.0-1.10.5XPotentially BenignThe sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the hydrophobic iso-propyl side chain of Val494, which is of a similar size and has similar physicochemical properties to Ile494 in the WT, resides similarly in the inter-helix hydrophobic space. Thus, no negative effects on the protein structure are observed.
c.2704G>AA902TLikely BenignLikely Benign 16-33443256-G-A362.23e-5-4.966Likely Benign0.116Likely BenignLikely Benign0.075Likely Benign-1.11Neutral0.951Possibly Damaging0.617Possibly Damaging2.61Benign0.01Affected3.77510-2.530.03
c.53A>GY18CLikely BenignUncertain 16-33420317-A-G442.88e-5-2.658Likely Benign0.251Likely BenignLikely Benign0.102Likely Benign-0.56Neutral0.872Possibly Damaging0.206Benign4.04Benign0.00Affected4.3210-23.8-60.04
c.4021G>AA1341TLikely BenignConflicting 36-33451895-G-A453.44e-5-3.224Likely Benign0.081Likely BenignLikely Benign0.099Likely Benign-0.58Neutral0.000Benign0.000Benign4.09Benign0.03Affected3.77510-2.530.03
c.3638A>CN1213TLikely BenignCoiled-coilConflicting 26-33446630-A-C462.85e-5-5.428Likely Benign0.266Likely BenignLikely Benign0.097Likely Benign-1.08Neutral0.959Probably Damaging0.721Possibly Damaging2.74Benign1.00Tolerated3.775002.8-13.00
c.1888A>GI630V
(3D Viewer)
GAPBenign/Likely benign 46-33440940-A-G593.66e-5-7.264In-Between0.145Likely BenignLikely Benign0.143Likely Benign1.33Ambiguous0.00.94Ambiguous1.14Ambiguous0.64Ambiguous-0.38Neutral0.018Benign0.011Benign-1.37Pathogenic0.35Tolerated3.373443-0.3-14.03235.026.2-0.10.0-0.30.1XPotentially BenignThe sec-butyl side chain of Ile630, located in an α helix (res. Glu617-Asn635), packs with hydrophobic residues (e.g., Phe594, Leu633, Ile626, Ile602) in the hydrophobic inter-helix space between two α helices (res. Glu617-Asn635 and res. Glu582-Met603).In the variant simulations, the iso-propyl side chain of Val630, which shares a similar size and physicochemical properties with Ile630 in the WT, maintains similar interactions in the inter-helix space. Although no negative structural effects are observed during the simulations, the implications of the residue swap on the complex formation with the GTPase, due to its location, cannot be investigated using solvent-only simulations.
c.3355G>AG1119RBenign 16-33443907-G-A644.23e-5-8.489Likely Pathogenic0.473AmbiguousLikely Benign0.303Likely Benign0.10Neutral0.969Probably Damaging0.462Possibly Damaging4.03Benign0.10Tolerated4.322-3-2-4.199.14
c.1285C>TR429W
(3D Viewer)
GAPConflicting 56-33438190-C-T654.03e-5-10.666Likely Pathogenic0.500AmbiguousLikely Benign0.282Likely Benign0.31Likely Benign0.1-0.13Likely Benign0.09Likely Benign0.52Ambiguous-3.19Deleterious1.000Probably Damaging0.990Probably Damaging3.41Benign0.03Affected3.38252-33.630.03252.345.50.00.00.20.1XPotentially PathogenicThe guanidinium group of Arg429, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or a H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, the indole ring of the Trp429 side chain cannot form ionic interactions with the acidic residues. Although it forms a H-bond with Ser471, the bonding is not as strong as that of arginine. The residue swap could affect the tertiary structure assembly during folding; however, no large-scale negative effects were seen during the simulations.
c.3056G>AR1019HLikely BenignConflicting 26-33443608-G-A674.15e-5-4.610Likely Benign0.258Likely BenignLikely Benign0.122Likely Benign-1.95Neutral0.995Probably Damaging0.845Possibly Damaging2.39Pathogenic0.01Affected3.775201.3-19.05
c.3175G>AG1059RUncertain 16-33443727-G-A684.23e-5-8.452Likely Pathogenic0.376AmbiguousLikely Benign0.333Likely Benign-0.55Neutral0.001Benign0.001Benign2.53Benign0.00Affected4.322-3-2-4.199.14
c.2369C>AT790NSH3-binding motifConflicting 36-33442921-C-A694.28e-5-5.243Likely Benign0.276Likely BenignLikely Benign0.103Likely Benign-2.54Deleterious0.999Probably Damaging0.997Probably Damaging2.27Pathogenic0.02Affected3.64600-2.813.00
c.2381C>TP794LLikely BenignSH3-binding motifBenign/Likely benign 26-33442933-C-T734.52e-5-3.808Likely Benign0.079Likely BenignLikely Benign0.075Likely Benign-0.80Neutral0.761Possibly Damaging0.321Benign4.24Benign0.03Affected4.073-3-35.416.04
c.2710A>GM904VLikely BenignLikely Benign 26-33443262-A-G774.78e-5-2.907Likely Benign0.112Likely BenignLikely Benign0.058Likely Benign-0.33Neutral0.039Benign0.023Benign2.80Benign0.10Tolerated3.775212.3-32.06
c.2864C>TS955FConflicting 46-33443416-C-T955.89e-5-7.374In-Between0.176Likely BenignLikely Benign0.093Likely Benign-1.73Neutral0.977Probably Damaging0.721Possibly Damaging2.32Pathogenic0.00Affected3.775-3-23.660.10
c.3172G>AG1058SLikely BenignConflicting 36-33443724-G-A1147.08e-5-5.178Likely Benign0.081Likely BenignLikely Benign0.108Likely Benign0.26Neutral0.001Benign0.001Benign5.38Benign0.04Affected3.77510-0.430.03
c.2845G>AG949SLikely BenignBenign/Likely benign 46-33443397-G-A1227.56e-5-5.693Likely Benign0.072Likely BenignLikely Benign0.321Likely Benign0.30Neutral0.611Possibly Damaging0.102Benign2.23Pathogenic0.00Affected4.32410-0.430.0310.1016/j.ajhg.2020.11.011
c.3858A>TE1286DLikely BenignConflicting 46-33447906-A-T1439.22e-5-4.010Likely Benign0.081Likely BenignLikely Benign0.036Likely Benign1.02Neutral0.001Benign0.004Benign2.96Benign1.00Tolerated3.775320.0-14.0310.1016/j.ajhg.2020.11.011
c.1724G>AR575H
(3D Viewer)
GAPConflicting 46-33440776-G-A2041.27e-4-11.142Likely Pathogenic0.496AmbiguousLikely Benign0.707Likely Pathogenic0.81Ambiguous0.2-0.22Likely Benign0.30Likely Benign1.31Destabilizing-2.34Neutral1.000Probably Damaging0.998Probably Damaging-1.33Pathogenic0.05Affected3.3735201.3-19.05244.780.60.00.00.30.0XPotentially PathogenicThe guanidinium group of Arg575, located in an α-helix (res. Arg563-Glu578), forms salt bridges with the carboxylate groups of Asp463 and Asp467, and it also hydrogen bonds with the hydroxyl group of Ser466 on an opposing α-helix (res. Ala461-Phe476) in the WT simulations. In the variant simulations, the imidazole ring of His575 (in its neutral epsilon protonated form) cannot form the same salt bridges as the guanidinium group of the non-mutated Arg575. Instead, His575 only forms weak hydrogen bonds with the hydroxyl groups of Ser466 and Ser571. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process.
c.3134C>GA1045GLikely BenignBenign/Likely benign 76-33443686-C-G14078.72e-4-3.246Likely Benign0.075Likely BenignLikely Benign0.024Likely Benign-1.21Neutral0.224Benign0.066Benign2.64Benign0.33Tolerated3.77510-2.2-14.0310.1016/j.ajhg.2020.11.011
c.3344T>CI1115TLikely BenignBenign 96-33443896-T-C205361.36e-2-2.670Likely Benign0.068Likely BenignLikely Benign0.100Likely Benign-0.04Neutral0.000Benign0.001Benign2.76Benign0.23Tolerated4.3220-1-5.2-12.05

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