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GeneBe

rs5443

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -4.90
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]
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]

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ACMG classification

Classification made for transcript

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
GNB3NM_002075.4 linkuse as main transcriptc.825C>T p.Ser275= synonymous_variant 9/10 ENST00000229264.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GNB3ENST00000229264.8 linkuse as main transcriptc.825C>T p.Ser275= synonymous_variant 9/105 NM_002075.4 P1P16520-1

Frequencies

GnomAD3 genomes
AF:
0.439
AC:
66665
AN:
151972
Hom.:
17391
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 14, 2018This 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. -
Congenital stationary night blindness 1H Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
GNB3 POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMApr 01, 2003- -
Hypertension, essential, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMApr 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

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

Other links and lift over

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