rs11045819

Variant names:

• chr12-21176879-C-A
• rs11045819
• NM_006446.5:c.463C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-21176879-C-A
• chr12-21176879-C-G
• chr12-21176879-C-T

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.463C>A​(p.Pro155Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,507,068 control chromosomes in the GnomAD database, including 11,786 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1313 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10473 hom.)
• Consequence: SLCO1B1 NM_006446.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.805
• Publications: 149 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

ENSG00000257062 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021197796).
• BP6: Variant 12-21176879-C-A is Benign according to our data. Variant chr12-21176879-C-A is described in ClinVar as Benign. ClinVar VariationId is 307937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B1	NM_006446.5	c.463C>A	p.Pro155Thr	missense_variant	Exon 5 of 15	ENST00000256958.3	NP_006437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B1	ENST00000256958.3	c.463C>A	p.Pro155Thr	missense_variant	Exon 5 of 15	1	NM_006446.5	ENSP00000256958.2
ENSG00000257062	ENST00000543498.5	n.*245C>A		non_coding_transcript_exon_variant	Exon 6 of 6	4		ENSP00000454306.1
ENSG00000257062	ENST00000543498.5	n.*245C>A		3_prime_UTR_variant	Exon 6 of 6	4		ENSP00000454306.1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18260 AN: 151792 Hom.: 1314 Cov.: 33

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.114 AC: 28564 AN: 250104 AF XY: 0.115

Gnomad AFR exome AF: 0.0766

Gnomad AMR exome AF: 0.0702

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.110 AC: 148526 AN: 1355158 Hom.: 10473 Cov.: 27 AF XY: 0.108 AC XY: 73343 AN XY: 677414

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0632 AC: 2037 AN: 32256

American (AMR) AF: 0.0670 AC: 2959 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4341 AN: 24628

East Asian (EAS) AF: 0.000279 AC: 11 AN: 39406

South Asian (SAS) AF: 0.0409 AC: 3490 AN: 85330

European-Finnish (FIN) AF: 0.0931 AC: 4792 AN: 51448

Middle Eastern (MID) AF: 0.0874 AC: 481 AN: 5504

European-Non Finnish (NFE) AF: 0.123 AC: 124477 AN: 1015686

Other (OTH) AF: 0.105 AC: 5938 AN: 56748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.120 AC: 18261 AN: 151910 Hom.: 1313 Cov.: 33 AF XY: 0.115 AC XY: 8524 AN XY: 74238

African (AFR) AF: 0.0785 AC: 3257 AN: 41468

American (AMR) AF: 0.100 AC: 1533 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 735 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.0416 AC: 200 AN: 4804

European-Finnish (FIN) AF: 0.104 AC: 1094 AN: 10536

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10789 AN: 67874

Other (OTH) AF: 0.111 AC: 235 AN: 2114

Alfa AF: 0.143 Hom.: 6194

Bravo AF: 0.121

TwinsUK AF: 0.169 AC: 627

ALSPAC AF: 0.158 AC: 609

ESP6500AA AF: 0.0860 AC: 379

ESP6500EA AF: 0.161 AC: 1379

ExAC AF: 0.117 AC: 14142

Asia WGS AF: 0.0240 AC: 82 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:3

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

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	0.065
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.2
DANN	Benign	0.69
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.81
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.025
Sift	Benign	0.16	T
Sift4G	Benign	0.47	T
Polyphen		0.0020	B
Vest4		0.10
MPC		0.012
ClinPred		0.0024	T
GERP RS		-3.4
Varity_R		0.11
gMVP		0.29
Mutation Taster		=97/3	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: rs11045819; hg19: chr12-21329813;