rs5443

chr12-6845711-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002075.4(GNB3):c.825C>T(p.Ser275=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,613,364 control chromosomes in the GnomAD database, including 100,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S275S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.44 (17424 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82938 hom.)
• Consequence: GNB3 NM_002075.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -4.90

Genes affected

GNB3 (HGNC:4400): (G protein subunit beta 3) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit which belongs to the WD repeat G protein beta family. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Jul 2014]

CDCA3 (HGNC:14624): (cell division cycle associated 3) Predicted to be involved in cell division and protein ubiquitination. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-6845711-C-T is Benign according to our data. Variant chr12-6845711-C-T is described in ClinVar as [Benign]. Clinvar id is 226004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB3	NM_002075.4	c.825C>T	p.Ser275=	synonymous_variant	9/10	ENST00000229264.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB3	ENST00000229264.8	c.825C>T	p.Ser275=	synonymous_variant	9/10	5	NM_002075.4	P1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66665 AN: 151972 Hom.: 17391 Cov.: 32

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.446

GnomAD3 exomes AF: 0.357 AC: 89686 AN: 251406 Hom.: 18076 AF XY: 0.347 AC XY: 47203 AN XY: 135908

Gnomad AFR exome AF: 0.756

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.524

Gnomad SAS exome AF: 0.320

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.326 AC: 476344 AN: 1461274 Hom.: 82938 Cov.: 35 AF XY: 0.325 AC XY: 236257 AN XY: 726988

Gnomad4 AFR exome AF: 0.764

Gnomad4 AMR exome AF: 0.356

Gnomad4 ASJ exome AF: 0.321

Gnomad4 EAS exome AF: 0.513

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.439 AC: 66758 AN: 152090 Hom.: 17424 Cov.: 32 AF XY: 0.434 AC XY: 32272 AN XY: 74342

Gnomad4 AFR AF: 0.738

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.508

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.450

Alfa AF: 0.338 Hom.: 16366

Bravo AF: 0.466

Asia WGS AF: 0.421 AC: 1461 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Congenital stationary night blindness 1H Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

GNB3 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Apr 01, 2003

- -

Hypertension, essential, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.22
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs5443; hg19: chr12-6954875; COSMIC: COSV57528272; COSMIC: COSV57528272;