12-21176827-G-A

Position:

• chr12-21176827-G-A

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.411G>A​(p.Ser137=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,505,436 control chromosomes in the GnomAD database, including 11,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1195 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10719 hom.)
• Consequence: SLCO1B1 NM_006446.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.153

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 (BayesDel_noAF=-0.9).
• BP6: Variant 12-21176827-G-A is Benign according to our data. Variant chr12-21176827-G-A is described in ClinVar as [Benign]. Clinvar id is 307936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21176827-G-A is described in Lovd as [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	Protein	UniProt
SLCO1B1	NM_006446.5	c.411G>A	p.Ser137=	synonymous_variant	5/15	ENST00000256958.3	NP_006437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1B1	ENST00000256958.3	c.411G>A	p.Ser137=	synonymous_variant	5/15	1	NM_006446.5	ENSP00000256958	P1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16488 AN: 151934 Hom.: 1196 Cov.: 33

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.106

GnomAD3 exomes AF: 0.111 AC: 27884 AN: 250236 Hom.: 2031 AF XY: 0.113 AC XY: 15345 AN XY: 135286

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.0683

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0433

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.114 AC: 153953 AN: 1353384 Hom.: 10719 Cov.: 26 AF XY: 0.112 AC XY: 75928 AN XY: 676984

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.0648

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.000255

Gnomad4 SAS exome AF: 0.0414

Gnomad4 FIN exome AF: 0.0928

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.108 AC: 16480 AN: 152052 Hom.: 1195 Cov.: 33 AF XY: 0.104 AC XY: 7697 AN XY: 74340

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.0961

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0415

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.104

Alfa AF: 0.146 Hom.: 2789

Bravo AF: 0.108

Asia WGS AF: 0.0190 AC: 67 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

SLCO1B1-related disorder Benign:1

Likely benign, no assertion criteria provided

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.8
DANN	Benign	0.60

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: rs11045818; hg19: chr12-21329761;