12-21176898-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_006446.5(SLCO1B1):c.481+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00162 in 1,547,080 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0086 ( 24 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 22 hom. )

Consequence

SLCO1B1
NM_006446.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 4.25

Publications

16 publications found

Variant links:

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

SLCO1B1 links:

ENSG00000257062 (HGNC:):

ENSG00000257062 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

BP6

Variant 12-21176898-G-T is Benign according to our data. Variant chr12-21176898-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 307938.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00862 (1311/152088) while in subpopulation AFR AF = 0.0297 (1233/41518). AF 95% confidence interval is 0.0283. There are 24 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B1	NM_006446.5 link	c.481+1G>T		splice_donor_variant, intron_variant	Intron 5 of 14	ENST00000256958.3	NP_006437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B1	ENST00000256958.3 link	c.481+1G>T		splice_donor_variant, intron_variant	Intron 5 of 14	1	NM_006446.5	ENSP00000256958.2
ENSG00000257062	ENST00000543498.5 link	n.*264G>T		downstream_gene_variant		4		ENSP00000454306.1

Frequencies

GnomAD3 genomes

AF:

0.00861

AC:

1309

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00235

AC:

589

AN:

250278

AF XY:

0.00185

show subpopulations

Gnomad AFR exome

AF:

0.0312

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000797

Gnomad OTH exome

AF:

0.000657

GnomAD4 exome

AF:

0.000858

AC:

1197

AN:

1394992

Hom.:

Cov.:

AF XY:

0.000716

AC XY:

499

AN XY:

696988

show subpopulations

African (AFR)

AF:

0.0286

AC:

927

AN:

32450

American (AMR)

AF:

0.00238

AC:

106

AN:

44470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25340

East Asian (EAS)

AF:

0.00

AC:

AN:

39354

South Asian (SAS)

AF:

0.0000468

AC:

AN:

85490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52852

Middle Eastern (MID)

AF:

0.00179

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

0.0000285

AC:

AN:

1051334

Other (OTH)

AF:

0.00206

AC:

120

AN:

58122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00862

AC:

1311

AN:

152088

Hom.:

Cov.:

AF XY:

0.00818

AC XY:

608

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0297

AC:

1233

AN:

41518

American (AMR)

AF:

0.00334

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67938

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00304

Hom.:

Bravo

AF:

0.00959

ESP6500AA

AF:

0.0279

AC:

123

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.00288

AC:

350

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rotor syndrome

Pathogenic:1Uncertain:1Benign:1

Feb 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLCO1B1 c.481+1G>T variant (rs77271279) has not been reported in the literature in patients with Rotor syndrome but has been identified as a heterozygous variant in three unaffected individuals from one Rotor syndrome family (van de Steeg 2012). The unaffected individuals had at least one unmutated copy of SLCO1B3 and/or SLCO1B1. This variant is reported in ClinVar (Variation ID: 307938) and is found predominantly in the African/African-American population with an allele frequency of 3.0% (751/24,816 alleles, including 10 homozygotes) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice donor site of intron 5, which is likely to negatively impact gene function. In the context of a digenic recessive inheritance pattern, the clinical significance of this variant is uncertain at this time. References: van de Steeg E et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest. 2012 Feb. PMID: 22232210

SLCO1B1-related disorder

Uncertain:1

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SLCO1B1 c.481+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in both the heterozygous and compound heterozygous state with a 405 kb deletion (including exons 3-15 of SLCO1B3 and the entire SLCO1B1 gene) in unaffected members of a family with Rotor syndrome (Family A2, van de Steeg et al. 2012. PubMed ID: 22232210). Affected members of Family A2 were homozygous for the 405 kb deletion, demonstrating that only a complete deficiency of both alleles of SLCO1B1 and SLCO1B3 result in Rotor syndrome. In the gnomAD population database, this variant has been reported in 844 heterozygous and 10 homozygous individuals of unknown phenotype. In the ClinVar database, this variant has conflicting interpretations regarding its pathogenicity ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/307938/). At this time, the clinical significance of the c.481+1G>T variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.93

PhyloP100

4.3

GERP RS

3.5

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.84

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over