Genetic Variant NM_001321950.2:c.-46+14T>A (chr2-218260198-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001321950.2(GPBAR1):c.-46+14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,142 control chromosomes in the GnomAD database, including 18,016 homozygotes. 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: 𝑓 0.45 ( 18012 hom., cov: 33)

Exomes 𝑓: 0.71 ( 4 hom. )

Consequence

GPBAR1
NM_001321950.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.16

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPBAR1	NM_001321950.2 link	c.-46+14T>A		intron_variant	Intron 1 of 1		NP_001308879.1	Q8TDU6
GPBAR1	XM_011510743.1 link	c.-667+14T>A		intron_variant	Intron 1 of 1		XP_011509045.1	Q8TDU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPBAR1	ENST00000479077.5 link	c.-46+14T>A		intron_variant	Intron 1 of 1	2		ENSP00000430698.1		Q8TDU6

Frequencies

GnomAD3 genomes

AF:

0.453

AC:

68796

AN:

152010

Hom.:

17989

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.413

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.490

Gnomad EAS

AF:

0.566

Gnomad SAS

AF:

0.625

Gnomad FIN

AF:

0.689

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.558

Gnomad OTH

AF:

0.446

GnomAD4 exome

AF:

0.714

AC:

AN:

Hom.:

Cov.:

AF XY:

0.800

AC XY:

AN XY:

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:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), 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 Hom

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

AF:

0.453

AC:

68845

AN:

152128

Hom.:

18012

Cov.:

AF XY:

0.459

AC XY:

34112

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.176

AC:

7295

AN:

41510

American (AMR)

AF:

0.475

AC:

7259

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

1703

AN:

3472

East Asian (EAS)

AF:

0.566

AC:

2917

AN:

5154

South Asian (SAS)

AF:

0.625

AC:

3014

AN:

4826

European-Finnish (FIN)

AF:

0.689

AC:

7290

AN:

10584

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.558

AC:

37931

AN:

67988

Other (OTH)

AF:

0.449

AC:

947

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1700

3399

5099

6798

8498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.499

Hom.:

2574

Bravo

AF:

0.423

Asia WGS

AF:

0.606

AC:

2109

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.47

(source)

DANN

Benign

0.81

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over