9-77797577-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_002072.5(GNAQ):c.548G>A(p.Arg183Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
GNAQ
NM_002072.5 missense
NM_002072.5 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.86
Genes affected
GNAQ (HGNC:4390): (G protein subunit alpha q) This locus encodes a guanine nucleotide-binding protein. The encoded protein, an alpha subunit in the Gq class, couples a seven-transmembrane domain receptor to activation of phospolipase C-beta. Mutations at this locus have been associated with problems in platelet activation and aggregation. A related pseudogene exists on chromosome 2.[provided by RefSeq, Nov 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 9-77797577-C-T is Pathogenic according to our data. Variant chr9-77797577-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GNAQ | NM_002072.5 | c.548G>A | p.Arg183Gln | missense_variant | 4/7 | ENST00000286548.9 | NP_002063.2 | |
GNAQ | XM_047423239.1 | c.374G>A | p.Arg125Gln | missense_variant | 4/7 | XP_047279195.1 | ||
GNAQ | XM_047423240.1 | c.374G>A | p.Arg125Gln | missense_variant | 4/7 | XP_047279196.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Capillary malformation Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Oct 14, 2023 | A GNAQ c.548G>A (p.Arg183Gln) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with Sturge-Weber syndrome, nonsyndromic port-wine stains, and phakomatosis pigmentovascularis with capillary malformation and hemihypertrophy (Shirley MD et al., PMID: 23656586; Nakashima M et al., PMID: 25374402; Frigerio A et al., PMID: 26192947; Thomas AC et al., PMID: 26778290; He R et al., PMID: 32613723). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters (ClinVar ID: 50853), and it has been reported in multiple cases in the cancer database COSMIC (Genomic ID: COSV54106047). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the GTP-binding site of the G2 motif, which is defined as a critical functional domain (Nakashima M et al., PMID: 25374402). Computational predictors indicate that the GNAQ c.548G>A (p.Arg183Gln) variant is damaging, evidence that correlates with impact on GNAQ function. In support of this prediction, functional studies show that this variant increases activation of the mitogen-activated protein kinase (MAPK) pathway and increases angiopoietin-2 expression (Shirley MD et al., PMID: 23656586; Huang L et al., PMID: 34670408). GNAQ is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the GNAQ c.548G>A (p.Arg183Gln) variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
Segmental undergrowth associated with capillary malformation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical and Molecular Genetics, Hospital Universitario La Paz | Apr 06, 2021 | - - |
Familial multiple nevi flammei Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 07, 2022 | _x000D_ Criteria applied: PS3, PS4_MOD, PM2_SUP, PP3 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Aug 01, 2021 | This variant is a recurrent pathogenic variant that accounts for ~90% of individuals with non-syndromic port-wine stains and Sturge-Weber syndrome (MIM: 185300), which, along with congenital capillary malformations (MIM: 163000), is included within GNAQ-related disorder (PMID: 25374402, PMID: 23656586). - |
Sturge-Weber syndrome;C0340803:Capillary malformation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Jul 19, 2016 | This variant has been described in multiple affected individuals with a mosaic etiology (PMID 26778290) - |
Hemangiomatosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Angioosteohypertrophic syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
GNAQ-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Sep 19, 2024 | PS3_Moderate, PS4, PM1, PM2, PP3 - |
Sturge-Weber syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
Melanoma Uncertain:1
Uncertain significance, no assertion criteria provided | research | Dave Chen Lab, Washington University School of Medicine | Mar 28, 2023 | Somatic variant identified in a melanoma arising in a patient with Tatton-Brown Rahman Syndrome - |
Neoplasm Other:1
-, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of glycosylation at T186 (P = 0.1183);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at