NM_002075.4:c.814G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★).

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

Publications

59 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GNB3	NM_002075.4 link	c.814G>A	p.Gly272Ser	missense_variant	Exon 9 of 10	ENST00000229264.8	NP_002066.1	P16520-1F1T0G5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB3	ENST00000229264.8 link	c.814G>A	p.Gly272Ser	missense_variant	Exon 9 of 10	5	NM_002075.4	ENSP00000229264.3		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

GnomAD2 exomes

AF:

0.0484

AC:

12177

AN:

251402

AF XY:

0.0488

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 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

African (AFR)

AF:

0.00851

AC:

285

AN:

33478

American (AMR)

AF:

0.0277

AC:

1237

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0702

AC:

1836

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0148

AC:

1275

AN:

86258

European-Finnish (FIN)

AF:

0.0798

AC:

4262

AN:

53382

Middle Eastern (MID)

AF:

0.0468

AC:

270

AN:

5768

European-Non Finnish (NFE)

AF:

0.0686

AC:

76273

AN:

1111816

Other (OTH)

AF:

0.0569

AC:

3435

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

4539

9078

13616

18155

22694

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2764

5528

8292

11056

13820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0451

AC:

6868

AN:

152268

Hom.:

208

Cov.:

AF XY:

0.0441

AC XY:

3283

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0116

AC:

483

AN:

41544

American (AMR)

AF:

0.0417

AC:

638

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0720

AC:

249

AN:

3460

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00890

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0802

AC:

851

AN:

10610

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0657

AC:

4472

AN:

68018

Other (OTH)

AF:

0.0445

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

329

658

986

1315

1644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0578

Hom.:

1218

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

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21675276) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.;.

PhyloP100

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

Mutation Taster

=83/17

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over