2-218262852-G-A

Position:

chr2-218262852-G-A

Variant summary

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

The NM_170699.3(GPBAR1):c.128G>A(p.Arg43His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GPBAR1
NM_170699.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.53

Variant links:

Genes affected

GPBAR1 (HGNC:19680): (G protein-coupled bile acid receptor 1) This gene encodes a member of the G protein-coupled receptor (GPCR) superfamily. This enzyme functions as a cell surface receptor for bile acids. Treatment of cells expressing this GPCR with bile acids induces the production of intracellular cAMP, activation of a MAP kinase signaling pathway, and internalization of the receptor. The receptor is implicated in the suppression of macrophage functions and regulation of energy homeostasis by bile acids. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

GPBAR1 links:

Genome browser will be placed here

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=0.3148865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPBAR1	NM_170699.3 linkuse as main transcript	c.128G>A	p.Arg43His	missense_variant	2/2	ENST00000519574.2	NP_733800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GPBAR1	ENST00000519574.2 linkuse as main transcript	c.128G>A	p.Arg43His	missense_variant	2/2	1	NM_170699.3	ENSP00000430202	P1
GPBAR1	ENST00000479077.5 linkuse as main transcript	c.128G>A	p.Arg43His	missense_variant	2/2	2		ENSP00000430698	P1
GPBAR1	ENST00000521462.1 linkuse as main transcript	c.128G>A	p.Arg43His	missense_variant	2/2	2		ENSP00000428824	P1
GPBAR1	ENST00000522678.5 linkuse as main transcript	c.128G>A	p.Arg43His	missense_variant	2/2	2		ENSP00000430886	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247508

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134466

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461324

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The c.128G>A (p.R43H) alteration is located in exon 2 (coding exon 1) of the GPBAR1 gene. This alteration results from a G to A substitution at nucleotide position 128, causing the arginine (R) at amino acid position 43 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

GPBAR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2022

The GPBAR1 c.128G>A variant is predicted to result in the amino acid substitution p.Arg43His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219127575-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.45

T;T;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.72

.;.;.;T

M_CAP

Benign

0.0079

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;L;L

MutationTaster

Benign

0.54

N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Benign

0.083

Sift

Benign

0.13

T;T;T;T

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.096

B;B;B;B

Vest4

0.26

MutPred

0.77

Gain of catalytic residue at L45 (P = 0.0942);Gain of catalytic residue at L45 (P = 0.0942);Gain of catalytic residue at L45 (P = 0.0942);Gain of catalytic residue at L45 (P = 0.0942);

MVP

0.32

MPC

0.055

ClinPred

0.18

GERP RS

1.0

Varity_R

0.28

gMVP

0.31

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

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