rs7311358

Positions:

• chr12-20862826-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019844.4(SLCO1B3):​c.699G>A​(p.Met233Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.829 in 1,604,866 control chromosomes in the GnomAD database, including 559,664 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (42490 hom., cov: 32)
  • Exomes 𝑓: 0.84 (517174 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.26

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-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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4408281E-6).
• BP6: Variant 12-20862826-G-A is Benign according to our data. Variant chr12-20862826-G-A is described in ClinVar as [Benign]. Clinvar id is 261186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-20862826-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLCO1B3	NM_019844.4	c.699G>A	p.Met233Ile	missense_variant	8/16	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.699G>A	p.Met233Ile	missense_variant	6/16		NP_001358026.1
SLCO1B3	NM_001349920.2	c.615G>A	p.Met205Ile	missense_variant	6/14		NP_001336849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.699G>A	p.Met233Ile	missense_variant	8/16	2	NM_019844.4	ENSP00000370956.4
SLCO1B3-SLCO1B7	ENST00000540229.1	c.699G>A	p.Met233Ile	missense_variant	6/16	2		ENSP00000441269.1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110120 AN: 151890 Hom.: 42493 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.899

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.780

GnomAD3 exomes AF: 0.808 AC: 202789 AN: 250890 Hom.: 83630 AF XY: 0.823 AC XY: 111627 AN XY: 135606

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.802

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.724

Gnomad SAS exome AF: 0.905

Gnomad FIN exome AF: 0.755

Gnomad NFE exome AF: 0.854

Gnomad OTH exome AF: 0.827

GnomAD4 exome AF: 0.840 AC: 1220497 AN: 1452856 Hom.: 517174 Cov.: 29 AF XY: 0.844 AC XY: 610301 AN XY: 723358

Gnomad4 AFR exome AF: 0.415

Gnomad4 AMR exome AF: 0.803

Gnomad4 ASJ exome AF: 0.894

Gnomad4 EAS exome AF: 0.709

Gnomad4 SAS exome AF: 0.907

Gnomad4 FIN exome AF: 0.762

Gnomad4 NFE exome AF: 0.857

Gnomad4 OTH exome AF: 0.825

GnomAD4 genome AF: 0.725 AC: 110144 AN: 152010 Hom.: 42490 Cov.: 32 AF XY: 0.724 AC XY: 53774 AN XY: 74306

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.811

Gnomad4 ASJ AF: 0.890

Gnomad4 EAS AF: 0.720

Gnomad4 SAS AF: 0.900

Gnomad4 FIN AF: 0.747

Gnomad4 NFE AF: 0.853

Gnomad4 OTH AF: 0.780

Alfa AF: 0.815 Hom.: 39732

Bravo AF: 0.717

TwinsUK AF: 0.858 AC: 3180

ALSPAC AF: 0.853 AC: 3289

ESP6500AA AF: 0.448 AC: 1972

ESP6500EA AF: 0.864 AC: 7429

ExAC AF: 0.804 AC: 97653

Asia WGS AF: 0.763 AC: 2649 AN: 3472

EpiCase AF: 0.859

EpiControl AF: 0.865

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
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

Dec 29, 2021

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	0.17
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.5
DANN	Benign	0.90
DEOGEN2	Benign	0.065	.;T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.58	T;.;T;T;T
MetaRNN	Benign	0.0000014	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	.;N;N;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.45	T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.0070	.;B;B;.;.
Vest4		0.094, 0.10, 0.067
MutPred		0.46		Gain of catalytic residue at S228 (P = 3e-04);Gain of catalytic residue at S228 (P = 3e-04);Gain of catalytic residue at S228 (P = 3e-04);.;Gain of catalytic residue at S228 (P = 3e-04);
MPC		0.0069, 0.0096
ClinPred		0.0035	T
GERP RS		-2.0
Varity_R		0.10
gMVP		0.18

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

Other links and lift over

dbSNP: rs7311358; hg19: chr12-21015760; COSMIC: COSV53938010; COSMIC: COSV53938010;