12-20855051-C-G

Position:

chr12-20855051-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019844.4(SLCO1B3):c.108C>G(p.Phe36Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,611,122 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 6 hom. )

Consequence

SLCO1B3
NM_019844.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0330

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004777491).

BP6

Variant 12-20855051-C-G is Benign according to our data. Variant chr12-20855051-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 307885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00551 (839/152220) while in subpopulation AFR AF= 0.0197 (820/41536). AF 95% confidence interval is 0.0186. There are 13 homozygotes in gnomad4. There are 418 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLCO1B3	NM_019844.4 linkuse as main transcript	c.108C>G	p.Phe36Leu	missense_variant	4/16	ENST00000381545.8
SLCO1B3-SLCO1B7	NM_001371097.1 linkuse as main transcript	c.108C>G	p.Phe36Leu	missense_variant	2/16
SLCO1B3	NM_001349920.2 linkuse as main transcript	c.24C>G	p.Phe8Leu	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B3	ENST00000381545.8 linkuse as main transcript	c.108C>G	p.Phe36Leu	missense_variant	4/16	2	NM_019844.4	P1	Q9NPD5-1
SLCO1B3	ENST00000261196.6 linkuse as main transcript	c.108C>G	p.Phe36Leu	missense_variant	2/14	1		P1	Q9NPD5-1
SLCO1B3	ENST00000540853.5 linkuse as main transcript	c.108C>G	p.Phe36Leu	missense_variant	3/8	1
SLCO1B3	ENST00000545880.1 linkuse as main transcript			upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00552

AC:

839

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

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:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00149

AC:

373

AN:

249912

Hom.:

AF XY:

0.00104

AC XY:

140

AN XY:

135088

show subpopulations

Gnomad AFR exome

AF:

0.0203

Gnomad AMR exome

AF:

0.000938

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000883

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000605

AC:

882

AN:

1458902

Hom.:

Cov.:

AF XY:

0.000522

AC XY:

379

AN XY:

725710

show subpopulations

Gnomad4 AFR exome

AF:

0.0221

Gnomad4 AMR exome

AF:

0.000902

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00551

AC:

839

AN:

152220

Hom.:

Cov.:

AF XY:

0.00562

AC XY:

418

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0197

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000899

Hom.:

Bravo

AF:

0.00612

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0213

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00180

AC:

219

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rotor syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SLCO1B3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

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

Uncertain

0.35

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.6

DANN

Benign

0.88

DEOGEN2

Benign

0.32

.;T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.52

T;.;T;T;T

MetaRNN

Benign

0.0048

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.43

.;N;N;.;.

MutationTaster

Benign

0.96

D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.8

D;D;D;D;D

REVEL

Benign

0.058

Sift

Benign

0.14

T;T;T;T;T

Sift4G

Benign

0.38

T;T;T;T;T

Polyphen

0.078

.;B;B;.;.

Vest4

0.28, 0.28, 0.26, 0.29

MutPred

0.54

Gain of catalytic residue at S35 (P = 2e-04);Gain of catalytic residue at S35 (P = 2e-04);Gain of catalytic residue at S35 (P = 2e-04);Gain of catalytic residue at S35 (P = 2e-04);Gain of catalytic residue at S35 (P = 2e-04);

MVP

0.17

MPC

0.0071, 0.0085

ClinPred

0.022

GERP RS

1.9

Varity_R

0.34

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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