rs541676373

Variant names:

• chr9-77728672-A-G
• rs541676373
• NM_002072.5:c.736-5T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002072.5(GNAQ):​c.736-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000486 in 782,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: GNAQ NM_002072.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005036
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.572

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-77728672-A-G is Benign according to our data. Variant chr9-77728672-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3057817.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAQ	NM_002072.5	c.736-5T>C		splice_region_variant, intron_variant	Intron 5 of 6	ENST00000286548.9	NP_002063.2
GNAQ	XM_047423239.1	c.562-5T>C		splice_region_variant, intron_variant	Intron 5 of 6		XP_047279195.1
GNAQ	XM_047423240.1	c.562-5T>C		splice_region_variant, intron_variant	Intron 5 of 6		XP_047279196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAQ	ENST00000286548.9	c.736-5T>C		splice_region_variant, intron_variant	Intron 5 of 6	1	NM_002072.5	ENSP00000286548.4

Frequencies

GnomAD3 genomes AF: 0.000614 AC: 12 AN: 19530 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000640

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000172

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000952 AC: 34 AN: 35714 AF XY: 0.000893

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000746

Gnomad FIN exome AF: 0.000637

Gnomad NFE exome AF: 0.000847

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000341 AC: 26 AN: 763060 Hom.: 0 Cov.: 22 AF XY: 0.0000397 AC XY: 15 AN XY: 377780

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000349 AC: 4 AN: 11458

American (AMR) AF: 0.00 AC: 0 AN: 16742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11918

East Asian (EAS) AF: 0.000328 AC: 5 AN: 15244

South Asian (SAS) AF: 0.0000271 AC: 1 AN: 36888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3232

European-Non Finnish (NFE) AF: 0.0000212 AC: 13 AN: 612138

Other (OTH) AF: 0.000100 AC: 3 AN: 29874

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000614 AC: 12 AN: 19558 Hom.: 0 Cov.: 0 AF XY: 0.000825 AC XY: 8 AN XY: 9692

African (AFR) AF: 0.00121 AC: 10 AN: 8270

American (AMR) AF: 0.00 AC: 0 AN: 1438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 380

East Asian (EAS) AF: 0.000639 AC: 1 AN: 1564

South Asian (SAS) AF: 0.00 AC: 0 AN: 740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 24

European-Non Finnish (NFE) AF: 0.000172 AC: 1 AN: 5812

Other (OTH) AF: 0.00 AC: 0 AN: 266

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GNAQ-related disorder Benign:1

Apr 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.43
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0060
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

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Other links and lift over

dbSNP: rs541676373; hg19: chr9-80343588;