rs5442

chr12-6845700-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002075.4(GNB3):c.814G>A(p.Gly272Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 1,613,922 control chromosomes in the GnomAD database, including 3,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.045 (208 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3090 hom.)
• Consequence: GNB3 NM_002075.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 10.0

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004829645).
• BP6: Variant 12-6845700-G-A is Benign according to our data. Variant chr12-6845700-G-A is described in ClinVar as [Benign]. Clinvar id is 1170122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB3	NM_002075.4	c.814G>A	p.Gly272Ser	missense_variant	9/10	ENST00000229264.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB3	ENST00000229264.8	c.814G>A	p.Gly272Ser	missense_variant	9/10	5	NM_002075.4	P1

Frequencies

GnomAD3 genomes AF: 0.0452 AC: 6873 AN: 152150 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0418

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00909

Gnomad FIN AF: 0.0802

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0657

Gnomad OTH AF: 0.0455

GnomAD3 exomes AF: 0.0484 AC: 12177 AN: 251402 Hom.: 416 AF XY: 0.0488 AC XY: 6636 AN XY: 135900

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.0696

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0133

Gnomad FIN exome AF: 0.0792

Gnomad NFE exome AF: 0.0695

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0608 AC: 88879 AN: 1461654 Hom.: 3090 Cov.: 32 AF XY: 0.0596 AC XY: 43335 AN XY: 727134

Gnomad4 AFR exome AF: 0.00851

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0702

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.0798

Gnomad4 NFE exome AF: 0.0686

Gnomad4 OTH exome AF: 0.0569

GnomAD4 genome AF: 0.0451 AC: 6868 AN: 152268 Hom.: 208 Cov.: 32 AF XY: 0.0441 AC XY: 3283 AN XY: 74456

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.0417

Gnomad4 ASJ AF: 0.0720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.0802

Gnomad4 NFE AF: 0.0657

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0597 Hom.: 610

Bravo AF: 0.0420

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0681 AC: 586

ExAC AF: 0.0499 AC: 6059

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0665

EpiControl AF: 0.0702

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 21675276) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.097	T;T;T
Polyphen		0.97	D;D;.
Vest4		0.30
MPC		0.85
ClinPred		0.032	T
GERP RS		4.6
Varity_R		0.90
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5442; hg19: chr12-6954864; COSMIC: COSV57528327; COSMIC: COSV57528327;