rs782550076

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002075.4(GNB3):​c.32C>A​(p.Ala11Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GNB3
NM_002075.4 missense

Scores

3
8
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.04
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32671037).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNB3NM_002075.4 linkc.32C>A p.Ala11Glu missense_variant Exon 2 of 10 ENST00000229264.8 NP_002066.1 P16520-1F1T0G5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNB3ENST00000229264.8 linkc.32C>A p.Ala11Glu missense_variant Exon 2 of 10 5 NM_002075.4 ENSP00000229264.3 P16520-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461266
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726862
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Benign
-0.023
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.48
T;.;T;.;T
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.33
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
2.9
M;.;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.0
D;D;D;D;D
REVEL
Benign
0.13
Sift
Uncertain
0.0040
D;D;D;D;D
Sift4G
Benign
0.076
T;D;D;T;D
Polyphen
0.53
P;.;.;P;.
Vest4
0.60
MutPred
0.41
Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP
0.69
MPC
0.58
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.61
gMVP
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-6950483; API