Genetic Variant GPBAR1:p.Asn4Lys (chr2-218262736-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_170699.3(GPBAR1):c.12C>G(p.Asn4Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,130 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N4N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GPBAR1
NM_170699.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.03

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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity GPBAR_HUMAN

PM2

Very rare variant in population databases, with high coverage;

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.12C>G	p.Asn4Lys	missense	Exon 2 of 2	NP_733800.1	Q8TDU6
GPBAR1	NM_001077191.2		c.12C>G	p.Asn4Lys	missense	Exon 2 of 2	NP_001070659.1	Q8TDU6
GPBAR1	NM_001077194.2		c.12C>G	p.Asn4Lys	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.12C>G	p.Asn4Lys	missense	Exon 2 of 2	ENSP00000430202.1	Q8TDU6
GPBAR1	ENST00000479077.5	TSL:2	c.12C>G	p.Asn4Lys	missense	Exon 2 of 2	ENSP00000430698.1	Q8TDU6
GPBAR1	ENST00000521462.1	TSL:2	c.12C>G	p.Asn4Lys	missense	Exon 2 of 2	ENSP00000428824.1	Q8TDU6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439130

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712918

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33124

American (AMR)

AF:

0.0000230

AC:

AN:

43530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25128

East Asian (EAS)

AF:

0.00

AC:

AN:

39194

South Asian (SAS)

AF:

0.00

AC:

AN:

84282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49716

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099060

Other (OTH)

AF:

0.00

AC:

AN:

59398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.52

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

PhyloP100

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

REVEL

Benign

0.083

Sift

Uncertain

0.012

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.56

MutPred

0.16

Gain of ubiquitination at N4 (P = 0.0014)

MVP

0.33

MPC

0.32

ClinPred

0.66

GERP RS

2.8

Varity_R

0.11

gMVP

0.50

Mutation Taster

=84/16

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