rs57325543

Positions:

chr12-20855097-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_019844.4(SLCO1B3):c.154A>G(p.Ile52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,612,072 control chromosomes in the GnomAD database, including 4 homozygotes. 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 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 3 hom. )

Consequence

SLCO1B3
NM_019844.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 1.90

Variant links:

Genes affected

SLCO1B3 (HGNC:10961): (solute carrier organic anion transporter family member 1B3) This gene encodes a liver-specific member of the organic anion transporter family. The encoded protein is a transmembrane receptor that mediates the sodium-independent uptake of endogenous and xenobiotic compounds and plays a critical role in bile acid and bilirubin transport. Mutations in this gene are a cause of Rotor type hyperbilirubinemia. Alternative splicing of this gene and the use of alternative promoters results in transcript variants encoding different isoforms that differ in their tissue specificity. [provided by RefSeq, Mar 2017]

SLCO1B3 links:

SLCO1B3-SLCO1B7 (HGNC:54403): (SLCO1B3-SLCO1B7 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring SLCO1B3 (solute carrier organic anion transporter family member 1B3) and SLCO1B7 (solute carrier organic anion transporter family member 1B7 (putative)) genes on chromosome 12. The readthrough transcript encodes a protein that shares sequence identity with both the upstream and downstream genes. [provided by RefSeq, Jun 2019]

SLCO1B3-SLCO1B7 links:

SLCO1B3 (HGNC:):

SLCO1B3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013580769).

BS2

High Homozygotes in GnomAdExome4 at 3 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLCO1B3	NM_019844.4 linkuse as main transcript	c.154A>G	p.Ile52Val	missense_variant	4/16	ENST00000381545.8	NP_062818.1	Q9NPD5-1B3KP78
SLCO1B3-SLCO1B7	NM_001371097.1 linkuse as main transcript	c.154A>G	p.Ile52Val	missense_variant	2/16		NP_001358026.1
SLCO1B3	NM_001349920.2 linkuse as main transcript	c.70A>G	p.Ile24Val	missense_variant	2/14		NP_001336849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8 linkuse as main transcript	c.154A>G	p.Ile52Val	missense_variant	4/16	2	NM_019844.4	ENSP00000370956.4		Q9NPD5-1
SLCO1B3-SLCO1B7	ENST00000540229.1 linkuse as main transcript	c.154A>G	p.Ile52Val	missense_variant	2/16	2		ENSP00000441269.1		A0A0A6YYJ9

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

348

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00803

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000558

AC:

140

AN:

250900

Hom.:

AF XY:

0.000428

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00839

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1459756

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

129

AN XY:

726256

show subpopulations

Gnomad4 AFR exome

AF:

0.00778

Gnomad4 AMR exome

AF:

0.000157

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:

0.00000180

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.00228

AC:

348

AN:

152316

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00801

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000397

Hom.:

Bravo

AF:

0.00266

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000766

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rotor syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 11, 2020

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Oct 11, 2016

- -

SLCO1B3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;T;T;.;.

Eigen

Benign

0.079

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

T;.;T;T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.7

.;M;M;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.82

N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.063

T;D;D;D;D

Sift4G

Benign

0.063

T;T;T;T;T

Polyphen

0.37

.;B;B;.;.

Vest4

0.39, 0.40, 0.40, 0.31

MVP

0.22

MPC

0.012, 0.011

ClinPred

0.065

GERP RS

3.8

Varity_R

0.18

gMVP

0.26

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