NM_002072.5:c.626A>T

Variant names:

• chr9-77794572-T-A
• rs121913492
• NM_002072.5:c.626A>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_002072.5(GNAQ):​c.626A>T​(p.Gln209Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAQ NM_002072.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a modified_residue 5-glutamyl histamine (size 0) in uniprot entity GNAQ_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-77794572-T-A is Pathogenic according to our data. Variant chr9-77794572-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 375955.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAQ	NM_002072.5	c.626A>T	p.Gln209Leu	missense_variant	Exon 5 of 7	ENST00000286548.9	NP_002063.2
GNAQ	XM_047423239.1	c.452A>T	p.Gln151Leu	missense_variant	Exon 5 of 7		XP_047279195.1
GNAQ	XM_047423240.1	c.452A>T	p.Gln151Leu	missense_variant	Exon 5 of 7		XP_047279196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAQ	ENST00000286548.9	c.626A>T	p.Gln209Leu	missense_variant	Exon 5 of 7	1	NM_002072.5	ENSP00000286548.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sturge-Weber syndrome Pathogenic:1

Dec 18, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A GNAQ c.626A>T (p.Gln209Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with various forms of nevi (Bender RP et al., PMID: 23599145; Colebatch AJ et al., PMID: 35439782; Van Raamsdonk CD et al., PMID: 19078957) and has been reported in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV54105914). This variant is absent from the general population database (gnomAD v4.0.0), indicating it is not a common variant. This variant resides within the GTP-binding site of the ras-like domain, amino acids 40-353, of GNAQ, which is defined as a critical functional domain (Markby DW et al., PMID: 8266082; Van Raamsdonk CD et al., PMID: 19078957). Computational predictors indicate that the GNAQ c.626A>T (p.Gln209Leu) variant is damaging, evidence that correlates with impact on GNAQ function. In support of this prediction, functional studies show increased activation of mitogen-activated protein kinase (MAPK) signaling pathways and associated downstream transcriptional programs leading to cellular transformation (Galeffi F et al., PMID: 35635655; Thomas AC et al., PMID: 26778290; Van Raamsdonk CD et al., PMID: 19078957). Other variants in the same codon, p.Gln209His, p.Gln209Arg and p.Gln209Pro, have been reported in multiple individuals and are considered pathogenic (Van Raamsdonk CD et al., PMID: 19078957; ClinVar IDs: 1172602, 1172601, 375956, 375957). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the GNAQ c.626A>T (p.Gln209Leu) variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.88		Loss of disorder (P = 0.0165);
MVP		0.91
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121913492; hg19: chr9-80409488; COSMIC: COSV54105914; COSMIC: COSV54105914;