rs34671512

Variant names:

• chr12-21239042-A-C
• rs34671512
• NM_006446.5:c.1929A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006446.5(SLCO1B1):​c.1929A>C​(p.Leu643Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0503 in 1,592,164 control chromosomes in the GnomAD database, including 2,239 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (241 hom., cov: 32)
  • Exomes 𝑓: 0.050 (1998 hom.)
• Consequence: SLCO1B1 NM_006446.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.965
• Publications: 48 publications found

Genes affected

SLCO1B1 (HGNC:10959): (solute carrier organic anion transporter family member 1B1) 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 numerous endogenous compounds including bilirubin, 17-beta-glucuronosyl estradiol and leukotriene C4. This protein is also involved in the removal of drug compounds such as statins, bromosulfophthalein and rifampin from the blood into the hepatocytes. Polymorphisms in the gene encoding this protein are associated with impaired transporter function. [provided by RefSeq, Mar 2009]

SLCO1B1 Gene-Disease associations (from GenCC):

• Rotor syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902895 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016977489).
• BP6: Variant 12-21239042-A-C is Benign according to our data. Variant chr12-21239042-A-C is described in ClinVar as Benign. ClinVar VariationId is 307959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B1	NM_006446.5	c.1929A>C	p.Leu643Phe	missense_variant	Exon 15 of 15	ENST00000256958.3	NP_006437.3
LOC124902895	XR_007063239.1	n.87-4743T>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B1	ENST00000256958.3	c.1929A>C	p.Leu643Phe	missense_variant	Exon 15 of 15	1	NM_006446.5	ENSP00000256958.2

Frequencies

GnomAD3 genomes AF: 0.0534 AC: 8124 AN: 152044 Hom.: 238 Cov.: 32

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0529

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0536

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0453 AC: 11209 AN: 247440 AF XY: 0.0461

Gnomad AFR exome AF: 0.0661

Gnomad AMR exome AF: 0.0355

Gnomad ASJ exome AF: 0.0634

Gnomad EAS exome AF: 0.000988

Gnomad FIN exome AF: 0.0394

Gnomad NFE exome AF: 0.0523

Gnomad OTH exome AF: 0.0447

GnomAD4 exome AF: 0.0500 AC: 72012 AN: 1440000 Hom.: 1998 Cov.: 27 AF XY: 0.0503 AC XY: 36059 AN XY: 717384

African (AFR) AF: 0.0660 AC: 2171 AN: 32896

American (AMR) AF: 0.0353 AC: 1573 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1632 AN: 25968

East Asian (EAS) AF: 0.000533 AC: 21 AN: 39430

South Asian (SAS) AF: 0.0457 AC: 3893 AN: 85098

European-Finnish (FIN) AF: 0.0406 AC: 2162 AN: 53208

Middle Eastern (MID) AF: 0.0605 AC: 343 AN: 5668

European-Non Finnish (NFE) AF: 0.0523 AC: 57158 AN: 1093600

Other (OTH) AF: 0.0513 AC: 3059 AN: 59576

GnomAD4 genome AF: 0.0535 AC: 8137 AN: 152164 Hom.: 241 Cov.: 32 AF XY: 0.0526 AC XY: 3913 AN XY: 74412

African (AFR) AF: 0.0641 AC: 2661 AN: 41528

American (AMR) AF: 0.0489 AC: 748 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5180

South Asian (SAS) AF: 0.0529 AC: 255 AN: 4820

European-Finnish (FIN) AF: 0.0347 AC: 367 AN: 10578

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0535 AC: 3640 AN: 67982

Other (OTH) AF: 0.0577 AC: 122 AN: 2116

Alfa AF: 0.0526 Hom.: 778

Bravo AF: 0.0539

TwinsUK AF: 0.0566 AC: 210

ALSPAC AF: 0.0547 AC: 211

ESP6500AA AF: 0.0635 AC: 277

ESP6500EA AF: 0.0559 AC: 478

ExAC AF: 0.0452 AC: 5481

Asia WGS AF: 0.0370 AC: 129 AN: 3472

EpiCase AF: 0.0590

EpiControl AF: 0.0584

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22147369) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

SLCO1B1-related disorder Benign:1

Jul 21, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	0.093
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.20
DANN	Benign	0.26
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.090	N
PhyloP100		-0.96
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.014
Sift	Benign	0.63	T
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.039
MutPred		0.20		Gain of methylation at K648 (P = 0.0775);
MPC		0.010
ClinPred		0.0028	T
GERP RS		-2.6
Varity_R		0.056
gMVP		0.16
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34671512; hg19: chr12-21391976;