rs5442

Positions:

chr12-6845700-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 10.0

Variant links:

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]

GNB3 links:

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]

CDCA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
GNB3	NM_002075.4 linkuse as main transcript	c.814G>A	p.Gly272Ser	missense_variant	9/10	ENST00000229264.8	NP_002066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB3	ENST00000229264.8 linkuse as main transcript	c.814G>A	p.Gly272Ser	missense_variant	9/10	5	NM_002075.4	ENSP00000229264	P1	P16520-1

Frequencies

GnomAD3 genomes

AF:

0.0452

AC:

6873

AN:

152150

Hom.:

209

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0596

AC XY:

43335

AN XY:

727134

show subpopulations

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.:

AF XY:

0.0441

AC XY:

3283

AN XY:

74456

show subpopulations

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:

ESP6500EA

AF:

0.0681

AC:

586

ExAC

AF:

0.0499

AC:

6059

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0665

EpiControl

AF:

0.0702

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 21675276) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0048

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.4

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over