chr12-20875274-G-C

Position:

chr12-20875274-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBA1

The NM_019844.4(SLCO1B3):c.767G>C(p.Gly256Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,612,444 control chromosomes in the GnomAD database, including 16,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1132 hom., cov: 32)

Exomes 𝑓: 0.13 ( 14884 hom. )

Consequence

SLCO1B3
NM_019844.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.83

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:):

SLCO1B3-SLCO1B7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.003154099).

BP6

Variant 12-20875274-G-C is Benign according to our data. Variant chr12-20875274-G-C is described in ClinVar as [Benign]. Clinvar id is 307896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLCO1B3	NM_019844.4 linkuse as main transcript	c.767G>C	p.Gly256Ala	missense_variant	9/16	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1 linkuse as main transcript	c.767G>C	p.Gly256Ala	missense_variant	7/16		NP_001358026.1
SLCO1B3	NM_001349920.2 linkuse as main transcript	c.683G>C	p.Gly228Ala	missense_variant	7/14		NP_001336849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8 linkuse as main transcript	c.767G>C	p.Gly256Ala	missense_variant	9/16	2	NM_019844.4	ENSP00000370956	P1	Q9NPD5-1
SLCO1B3	ENST00000261196.6 linkuse as main transcript	c.767G>C	p.Gly256Ala	missense_variant	7/14	1		ENSP00000261196	P1	Q9NPD5-1
SLCO1B3	ENST00000540853.5 linkuse as main transcript	c.767G>C	p.Gly256Ala	missense_variant	8/8	1		ENSP00000442000
SLCO1B3	ENST00000544370.1 linkuse as main transcript	c.239G>C	p.Gly80Ala	missense_variant	3/10	5		ENSP00000443225

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15920

AN:

151906

Hom.:

1134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0291

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0678

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.138

GnomAD3 exomes

AF:

0.112

AC:

28155

AN:

250862

Hom.:

2086

AF XY:

0.116

AC XY:

15769

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.0739

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.000545

Gnomad SAS exome

AF:

0.0696

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.142

GnomAD4 exome

AF:

0.134

AC:

195800

AN:

1460420

Hom.:

14884

Cov.:

AF XY:

0.134

AC XY:

97076

AN XY:

726574

show subpopulations

Gnomad4 AFR exome

AF:

0.0249

Gnomad4 AMR exome

AF:

0.0771

Gnomad4 ASJ exome

AF:

0.197

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.0676

Gnomad4 FIN exome

AF:

0.106

Gnomad4 NFE exome

AF:

0.149

Gnomad4 OTH exome

AF:

0.132

GnomAD4 genome

AF:

0.105

AC:

15914

AN:

152024

Hom.:

1132

Cov.:

AF XY:

0.100

AC XY:

7456

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0291

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.193

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0681

Gnomad4 FIN

AF:

0.102

Gnomad4 NFE

AF:

0.154

Gnomad4 OTH

AF:

0.136

Alfa

AF:

0.127

Hom.:

494

Bravo

AF:

0.104

TwinsUK

AF:

0.146

AC:

540

ALSPAC

AF:

0.147

AC:

566

ESP6500AA

AF:

0.0325

AC:

143

ESP6500EA

AF:

0.156

AC:

1344

ExAC

AF:

0.113

AC:

13739

Asia WGS

AF:

0.0330

AC:

114

AN:

3478

EpiCase

AF:

0.163

EpiControl

AF:

0.170

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rotor syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;T;T;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;.;D;D;D

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

3.9

.;H;H;.;.

MutationTaster

Benign

0.000098

P;P;P;P

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.6

D;D;D;D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D

Polyphen

1.0

.;D;D;.;.

Vest4

0.87, 0.31

MPC

0.035, 0.047

ClinPred

0.064

GERP RS

3.9

Varity_R

0.97

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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