Variant 3-179401295-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021629.4(GNB4):c.941G>A(p.Arg314His) variant causes a missense change. The variant allele was found at a frequency of 0.00000959 in 1,460,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GNB4
NM_021629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.11

Variant links:

Genes affected

GNB4 (HGNC:20731): (G protein subunit beta 4) 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. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. [provided by RefSeq, Jul 2008]

GNB4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB4	NM_021629.4 linkuse as main transcript	c.941G>A	p.Arg314His	missense_variant	10/10	ENST00000232564.8	NP_067642.1	Q9HAV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB4	ENST00000232564.8 linkuse as main transcript	c.941G>A	p.Arg314His	missense_variant	10/10	1	NM_021629.4	ENSP00000232564.3		Q9HAV0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250234

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135262

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1460292

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726460

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000611

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The p.R314H variant (also known as c.941G>A), located in coding exon 9 of the GNB4 gene, results from a G to A substitution at nucleotide position 941. The arginine at codon 314 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease dominant intermediate F

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNB4 protein function. ClinVar contains an entry for this variant (Variation ID: 1016177). This variant has not been reported in the literature in individuals affected with GNB4-related conditions. This variant is present in population databases (rs747095396, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 314 of the GNB4 protein (p.Arg314His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.70

MVP

0.70

MPC

1.6

ClinPred

1.0

GERP RS

4.0

Varity_R

0.74

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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