NM_002072.5:c.627A>C

Variant names:

• chr9-77794571-T-G
• NM_002072.5:c.627A>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002072.5(GNAQ):​c.627A>C​(p.Gln209His) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAQ NM_002072.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.0700

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 16 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, 0.976
• PP5: Variant 9-77794571-T-G is Pathogenic according to our data. Variant chr9-77794571-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1172601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAQ	NM_002072.5	c.627A>C	p.Gln209His	missense_variant	Exon 5 of 7	ENST00000286548.9	NP_002063.2
GNAQ	XM_047423239.1	c.453A>C	p.Gln151His	missense_variant	Exon 5 of 7		XP_047279195.1
GNAQ	XM_047423240.1	c.453A>C	p.Gln151His	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.627A>C	p.Gln209His	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial multiple nevi flammei Pathogenic:1

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 11, 2021

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has previously been reported as a somatic change in patients with vascular anomalies (PMID: 27058448, PMID: 30677207, PMID: ), and is absent from large population databases (Genome Aggregation Database v2.1.1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Benign	-0.0018
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.91	P
Vest4		0.78
MutPred		0.91		Gain of disorder (P = 0.093);
MVP		0.95
MPC		2.4
ClinPred		1.0	D
GERP RS		-3.4
Varity_R		0.91
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-80409487; COSMIC: COSV54109650; COSMIC: COSV54109650;