9-77794572-TG-AA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PM5 PP3 PP5

The NM_002072.5(GNAQ):c.625_626delinsTT(p.Gln209Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q209P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAQ NM_002072.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0

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 12 ACMG points.

• PS1: Transcript NM_002072.5 (GNAQ) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 375955
• PM1: In a modified_residue Deamidated glutamine; by Photorhabdus PAU_02230 (size 0) in uniprot entity GNAQ_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_002072.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-77794571-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1172602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-77794572-TG-AA is Pathogenic according to our data. Variant chr9-77794572-TG-AA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376311.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAQ	NM_002072.5	c.625_626delinsTT	p.Gln209Leu	missense_variant	5/7	ENST00000286548.9
GNAQ	XM_047423239.1	c.451_452delinsTT	p.Gln151Leu	missense_variant	5/7
GNAQ	XM_047423240.1	c.451_452delinsTT	p.Gln151Leu	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAQ	ENST00000286548.9	c.625_626delinsTT	p.Gln209Leu	missense_variant	5/7	1	NM_002072.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Uveal melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519853; hg19: chr9-80409488; COSMIC: COSV54109032;