rs71581941

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 20P and 5B. PVS1PS3PP5_Very_StrongBS1_SupportingBS2

The NM_006446.5(SLCO1B1):c.1738C>T(p.Arg580*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915589: The predicted truncation results in the loss of half of two transmembrane domains as well as a cytoplasmic tail, which may affect transport activity (Kim et al. 2007).". Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 18)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

SLCO1B1
NM_006446.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.885

Publications

33 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000915589: The predicted truncation results in the loss of half of two transmembrane domains as well as a cytoplasmic tail, which may affect transport activity (Kim et al. 2007).

PP5

Variant 12-21222355-C-T is Pathogenic according to our data. Variant chr12-21222355-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00132 (711/538442) while in subpopulation MID AF = 0.0208 (32/1542). AF 95% confidence interval is 0.0151. There are 2 homozygotes in GnomAdExome4. There are 377 alleles in the male GnomAdExome4 subpopulation. Median coverage is 12. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006446.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B1	NM_006446.5	MANE Select	c.1738C>T	p.Arg580*	stop_gained	Exon 13 of 15	NP_006437.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLCO1B1	ENST00000256958.3	TSL:1 MANE Select	c.1738C>T	p.Arg580*	stop_gained	Exon 13 of 15	ENSP00000256958.2	Q9Y6L6
SLCO1B1	ENST00000870182.1		c.1738C>T	p.Arg580*	stop_gained	Exon 14 of 16	ENSP00000540241.1
SLCO1B1	ENST00000870184.1		c.1738C>T	p.Arg580*	stop_gained	Exon 14 of 16	ENSP00000540243.1

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

158

AN:

95992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000971

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00331

Gnomad ASJ

AF:

0.00268

Gnomad EAS

AF:

0.00400

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00183

Gnomad MID

AF:

0.0833

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.00409

GnomAD2 exomes

AF:

0.00164

AC:

297

AN:

181496

AF XY:

0.00170

show subpopulations

Gnomad AFR exome

AF:

0.000832

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.00205

Gnomad EAS exome

AF:

0.00424

Gnomad FIN exome

AF:

0.000876

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00132

AC:

711

AN:

538442

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

377

AN XY:

272138

show subpopulations

African (AFR)

AF:

0.00163

AC:

AN:

12250

American (AMR)

AF:

0.00291

AC:

AN:

22682

Ashkenazi Jewish (ASJ)

AF:

0.00152

AC:

AN:

11172

East Asian (EAS)

AF:

0.00362

AC:

AN:

14360

South Asian (SAS)

AF:

0.000746

AC:

AN:

30826

European-Finnish (FIN)

AF:

0.00127

AC:

AN:

29880

Middle Eastern (MID)

AF:

0.0208

AC:

AN:

1542

European-Non Finnish (NFE)

AF:

0.00104

AC:

409

AN:

394990

Other (OTH)

AF:

0.00260

AC:

AN:

20740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00162

AC:

156

AN:

96026

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

AN XY:

43466

show subpopulations

African (AFR)

AF:

0.000970

AC:

AN:

23706

American (AMR)

AF:

0.00330

AC:

AN:

6058

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

2990

East Asian (EAS)

AF:

0.00400

AC:

AN:

3248

South Asian (SAS)

AF:

0.00

AC:

AN:

2910

European-Finnish (FIN)

AF:

0.00183

AC:

AN:

2184

Middle Eastern (MID)

AF:

0.0652

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

52878

Other (OTH)

AF:

0.00408

AC:

AN:

1224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00119

Hom.:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00163

AC:

198

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Rotor syndrome (10)

not provided (1)

SLCO1B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.54

PhyloP100

0.89

Vest4

0.91

GERP RS

3.8

Mutation Taster

=135/65

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over