Genetic Variant GPBAR1:p.Pro12Thr (chr2-218262758-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_170699.3(GPBAR1):c.34C>A(p.Pro12Thr) 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 1,455,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GPBAR1
NM_170699.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.320

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05106294).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170699.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPBAR1	NM_170699.3	MANE Select	c.34C>A	p.Pro12Thr	missense	Exon 2 of 2	NP_733800.1	Q8TDU6
GPBAR1	NM_001077191.2		c.34C>A	p.Pro12Thr	missense	Exon 2 of 2	NP_001070659.1	Q8TDU6
GPBAR1	NM_001077194.2		c.34C>A	p.Pro12Thr	missense	Exon 2 of 2	NP_001070662.1	Q8TDU6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPBAR1	ENST00000519574.2	TSL:1 MANE Select	c.34C>A	p.Pro12Thr	missense	Exon 2 of 2	ENSP00000430202.1	Q8TDU6
GPBAR1	ENST00000479077.5	TSL:2	c.34C>A	p.Pro12Thr	missense	Exon 2 of 2	ENSP00000430698.1	Q8TDU6
GPBAR1	ENST00000521462.1	TSL:2	c.34C>A	p.Pro12Thr	missense	Exon 2 of 2	ENSP00000428824.1	Q8TDU6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723514

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33388

American (AMR)

AF:

0.00

AC:

AN:

44390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25902

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

85774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108796

Other (OTH)

AF:

0.00

AC:

AN:

60098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.7

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.044

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.51

M_CAP

Benign

0.0042

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

-0.32

PrimateAI

Benign

0.32

PROVEAN

Benign

0.090

REVEL

Benign

0.014

Sift

Uncertain

0.023

Sift4G

Uncertain

0.041

Polyphen

0.0

Vest4

0.24

MutPred

0.11

Gain of phosphorylation at P12 (P = 0.0534)

MVP

0.040

MPC

0.049

ClinPred

0.11

GERP RS

-1.7

Varity_R

0.066

gMVP

0.46

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over