12-20861014-C-T

Variant names:

• chr12-20861014-C-T
• rs3764009
• NM_019844.4:c.360-3C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019844.4(SLCO1B3):​c.360-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.828 in 1,552,940 control chromosomes in the GnomAD database, including 540,393 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (42467 hom., cov: 31)
  • Exomes 𝑓: 0.84 (497926 hom.)
• Consequence: SLCO1B3 NM_019844.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002759
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.436
• Publications: 14 publications found

Genes affected

SLCO1B3 (HGNC:10961): (solute carrier organic anion transporter family member 1B3) 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 endogenous and xenobiotic compounds and plays a critical role in bile acid and bilirubin transport. Mutations in this gene are a cause of Rotor type hyperbilirubinemia. Alternative splicing of this gene and the use of alternative promoters results in transcript variants encoding different isoforms that differ in their tissue specificity. [provided by RefSeq, Mar 2017]

SLCO1B3-SLCO1B7 (HGNC:54403): (SLCO1B3-SLCO1B7 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring SLCO1B3 (solute carrier organic anion transporter family member 1B3) and SLCO1B7 (solute carrier organic anion transporter family member 1B7 (putative)) genes on chromosome 12. The readthrough transcript encodes a protein that shares sequence identity with both the upstream and downstream genes. [provided by RefSeq, Jun 2019]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-20861014-C-T is Benign according to our data. Variant chr12-20861014-C-T is described in ClinVar as Benign. ClinVar VariationId is 261185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B3	NM_019844.4	c.360-3C>T		splice_region_variant, intron_variant	Intron 5 of 15	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.360-3C>T		splice_region_variant, intron_variant	Intron 3 of 15		NP_001358026.1
SLCO1B3	NM_001349920.2	c.276-3C>T		splice_region_variant, intron_variant	Intron 3 of 13		NP_001336849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.360-3C>T		splice_region_variant, intron_variant	Intron 5 of 15	2	NM_019844.4	ENSP00000370956.4
SLCO1B3-SLCO1B7	ENST00000540229.1	c.360-3C>T		splice_region_variant, intron_variant	Intron 3 of 15	2		ENSP00000441269.1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110072 AN: 151836 Hom.: 42470 Cov.: 31

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.897

Gnomad FIN AF: 0.746

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.781

GnomAD2 exomes AF: 0.803 AC: 177645 AN: 221244 AF XY: 0.818

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.789

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.715

Gnomad FIN exome AF: 0.754

Gnomad NFE exome AF: 0.852

Gnomad OTH exome AF: 0.826

GnomAD4 exome AF: 0.839 AC: 1175711 AN: 1400986 Hom.: 497926 Cov.: 31 AF XY: 0.843 AC XY: 588204 AN XY: 697890

African (AFR) AF: 0.409 AC: 12741 AN: 31188

American (AMR) AF: 0.795 AC: 28691 AN: 36084

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 22263 AN: 24930

East Asian (EAS) AF: 0.707 AC: 26990 AN: 38164

South Asian (SAS) AF: 0.906 AC: 71703 AN: 79146

European-Finnish (FIN) AF: 0.762 AC: 40402 AN: 53050

Middle Eastern (MID) AF: 0.873 AC: 4837 AN: 5542

European-Non Finnish (NFE) AF: 0.856 AC: 920171 AN: 1074742

Other (OTH) AF: 0.824 AC: 47913 AN: 58140

GnomAD4 genome AF: 0.725 AC: 110096 AN: 151954 Hom.: 42467 Cov.: 31 AF XY: 0.724 AC XY: 53732 AN XY: 74262

African (AFR) AF: 0.436 AC: 18038 AN: 41410

American (AMR) AF: 0.812 AC: 12390 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3089 AN: 3470

East Asian (EAS) AF: 0.721 AC: 3707 AN: 5144

South Asian (SAS) AF: 0.899 AC: 4335 AN: 4822

European-Finnish (FIN) AF: 0.746 AC: 7861 AN: 10540

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 57993 AN: 67990

Other (OTH) AF: 0.780 AC: 1646 AN: 2110

Alfa AF: 0.819 Hom.: 66482

Bravo AF: 0.717

Asia WGS AF: 0.764 AC: 2655 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:3

Jan 12, 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.67
PhyloP100		-0.44
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.090		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: rs3764009; hg19: chr12-21013948; COSMIC: COSV53938114; COSMIC: COSV53938114;