9-77728671-G-GAA

Variant names:

• chr9-77728671-G-GAA
• rs5898555
• NM_002072.5:c.736-6_736-5dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002072.5(GNAQ):​c.736-6_736-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,298,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.049 (0 hom.)
• Consequence: GNAQ NM_002072.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:4
• 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 -10 ACMG points.

• BP6: Variant 9-77728671-G-GAA is Benign according to our data. Variant chr9-77728671-G-GAA is described in ClinVar as [Benign]. Clinvar id is 770953.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0493 (56832/1153140) while in subpopulation NFE AF = 0.0535 (46969/877414). AF 95% confidence interval is 0.0531. There are 0 homozygotes in GnomAdExome4. There are 27878 alleles in the male GnomAdExome4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 208 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 207 AN: 145514 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00143

Gnomad ASJ AF: 0.000585

Gnomad EAS AF: 0.00303

Gnomad SAS AF: 0.000647

Gnomad FIN AF: 0.00391

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00151

GnomAD2 exomes AF: 0.0249 AC: 4251 AN: 170990 AF XY: 0.0248

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.0299

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.0178

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0329

GnomAD4 exome AF: 0.0493 AC: 56832 AN: 1153140 Hom.: 0 Cov.: 22 AF XY: 0.0482 AC XY: 27878 AN XY: 578696

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

African (AFR) AF: 0.0252 AC: 669 AN: 26580

American (AMR) AF: 0.0331 AC: 952 AN: 28736

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 814 AN: 20778

East Asian (EAS) AF: 0.0243 AC: 872 AN: 35896

South Asian (SAS) AF: 0.0406 AC: 2795 AN: 68776

European-Finnish (FIN) AF: 0.0344 AC: 1440 AN: 41814

Middle Eastern (MID) AF: 0.0360 AC: 161 AN: 4468

European-Non Finnish (NFE) AF: 0.0535 AC: 46969 AN: 877414

Other (OTH) AF: 0.0444 AC: 2160 AN: 48678

⚠️ 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: 0.00143 AC: 208 AN: 145580 Hom.: 0 Cov.: 0 AF XY: 0.00154 AC XY: 109 AN XY: 70566

African (AFR) AF: 0.00159 AC: 63 AN: 39610

American (AMR) AF: 0.00143 AC: 21 AN: 14682

Ashkenazi Jewish (ASJ) AF: 0.000585 AC: 2 AN: 3420

East Asian (EAS) AF: 0.00304 AC: 15 AN: 4934

South Asian (SAS) AF: 0.000650 AC: 3 AN: 4616

European-Finnish (FIN) AF: 0.00391 AC: 34 AN: 8702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00101 AC: 67 AN: 66428

Other (OTH) AF: 0.00150 AC: 3 AN: 2006

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jul 24, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism

Splicing

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: rs5898555; hg19: chr9-80343587;