12-6841310-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002075.4(GNB3):c.23G>A(p.Arg8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: GNB3 NM_002075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13906842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB3	NM_002075.4	c.23G>A	p.Arg8His	missense_variant	2/10	ENST00000229264.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB3	ENST00000229264.8	c.23G>A	p.Arg8His	missense_variant	2/10	5	NM_002075.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000642 AC: 16 AN: 249338 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134896

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000140 AC: 205 AN: 1461282 Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93 AN XY: 726858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74454

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000122 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 8 of the GNB3 protein (p.Arg8His). This variant is present in population databases (rs199531660, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GNB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 964467). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GNB3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	2.9	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.60	P;.;.;P;.
Vest4		0.40
MVP		0.40
MPC		0.39
ClinPred		0.51	D
GERP RS		2.9
Varity_R		0.26
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199531660; hg19: chr12-6950474; COSMIC: COSV99300977; COSMIC: COSV99300977;