Variant chr9-77797577-C-T details in Genebe, Genetics Data Aggregator

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1O:1

Conservation

PhyloP100: 7.86

Variant links:

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]

GNAQ links:

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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 link	c.548G>A	p.Arg183Gln	missense_variant	4/7	ENST00000286548.9	NP_002063.2	P50148A0A024R240
GNAQ	XM_047423239.1 link	c.374G>A	p.Arg125Gln	missense_variant	4/7		XP_047279195.1
GNAQ	XM_047423240.1 link	c.374G>A	p.Arg125Gln	missense_variant	4/7		XP_047279196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAQ	ENST00000286548.9 link	c.548G>A	p.Arg183Gln	missense_variant	4/7	1	NM_002072.5	ENSP00000286548.4		P50148
GNAQ	ENST00000411677.1 link	c.461G>A	p.Arg154Gln	missense_variant	4/4	3		ENSP00000391501.1		B1AM21

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

H;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.95

Gain of glycosylation at T186 (P = 0.1183);.;

MVP

0.98

MPC

2.6

ClinPred

1.0

GERP RS

5.9

Varity_R

0.94

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over