Genetic Variant GNAQ:c.736-9_736-5dupTTTTT (chr9-77728671-G-GAAAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002072.5(GNAQ):c.736-9_736-5dupTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000169 in 1,183,180 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAQ
NM_002072.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.572

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GNAQ	NM_002072.5 link	c.736-9_736-5dupTTTTT	splice_region_variant, intron_variant	Intron 5 of 6	ENST00000286548.9	NP_002063.2	P50148A0A024R240
GNAQ	XM_047423239.1 link	c.562-9_562-5dupTTTTT	splice_region_variant, intron_variant	Intron 5 of 6		XP_047279195.1
GNAQ	XM_047423240.1 link	c.562-9_562-5dupTTTTT	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 link	c.736-5_736-4insTTTTT		splice_region_variant, intron_variant	Intron 5 of 6	1	NM_002072.5	ENSP00000286548.4		P50148

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

145632

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000169

AC:

AN:

1183180

Hom.:

Cov.:

AF XY:

0.00000168

AC XY:

AN XY:

593628

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27002

American (AMR)

AF:

0.00

AC:

AN:

29394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21320

East Asian (EAS)

AF:

0.00

AC:

AN:

36630

South Asian (SAS)

AF:

0.00

AC:

AN:

70576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4560

European-Non Finnish (NFE)

AF:

0.00000222

AC:

AN:

900770

Other (OTH)

AF:

0.00

AC:

AN:

50004

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

145632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70542

African (AFR)

AF:

0.00

AC:

AN:

39516

American (AMR)

AF:

0.00

AC:

AN:

14682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.00

AC:

AN:

4946

South Asian (SAS)

AF:

0.00

AC:

AN:

4638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66500

Other (OTH)

AF:

0.00

AC:

AN:

1990

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.57

Splicing

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

Publications

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9-77728671-G-GAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over