rs11045819

chr12-21176879-C-Achr12-21176879-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P155L) has been classified as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.805

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 307937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21176879-C-A is described in Lovd as [Benign]. Variant chr12-21176879-C-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
SLCO1B1	NM_006446.5	c.463C>A	p.Pro155Thr	missense_variant	5/15	ENST00000256958.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B1	ENST00000256958.3	c.463C>A	p.Pro155Thr	missense_variant	5/15	1	NM_006446.5	P1

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

GnomAD3 exomes AF: 0.114 AC: 28564 AN: 250104 Hom.: 2073 AF XY: 0.115 AC XY: 15611 AN XY: 135230

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 SAS exome AF: 0.0432

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

Gnomad4 AFR exome AF: 0.0632

Gnomad4 AMR exome AF: 0.0670

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.000279

Gnomad4 SAS exome AF: 0.0409

Gnomad4 FIN exome AF: 0.0931

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.105

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

Gnomad4 AFR AF: 0.0785

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0416

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.111

Alfa AF: 0.145 Hom.: 2888

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/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

SLCO1B1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2021

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
MutationTaster	Benign	1.0	P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11045819; hg19: chr12-21329813;