rs183501729
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2
The NM_006446.5(SLCO1B1):c.757C>T(p.Arg253Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
SLCO1B1
NM_006446.5 stop_gained
NM_006446.5 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 3.24
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM4
?
Stoplost variant in NM_006446.5 Downstream stopcodon found after 725 codons.
BS2
?
High AC in GnomAd at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLCO1B1 | NM_006446.5 | c.757C>T | p.Arg253Ter | stop_gained | 8/15 | ENST00000256958.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLCO1B1 | ENST00000256958.3 | c.757C>T | p.Arg253Ter | stop_gained | 8/15 | 1 | NM_006446.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152080Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251156Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135764
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GnomAD4 exome AF: 0.0000452 AC: 66AN: 1461222Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 726922
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rotor syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 09, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000030439 / PMID: 22232210). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 09, 2022 | Variant summary: SLCO1B1 c.757C>T (p.Arg253X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6e-05 in 251156 control chromosomes (gnomAD). This frequency does not allow conclusions about the variant significance. SLCO1B1 c.757C>T (p.Arg253X) (along with SLCO1B3, c.1747+1G>A) has been reported in the literature in individuals affected with Rotor Syndrome which supports the digenic recessive inheritance of the disease (examples: van de Steeg_2012, Chen_2019, and Zhou_2020). It has been shown that digenic pathogenic variants in SLCO1B1 and SLCO1B3 cause Rotor syndrome (GeneReviews, NCBI Bookshelf). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2012 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at