NM_019844.4:c.728-76T>C

Variant names:

• chr12-20875159-T-C
• rs3829311
• NM_019844.4:c.728-76T>C

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.728-76T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 1,511,252 control chromosomes in the GnomAD database, including 474,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (36472 hom., cov: 31)
  • Exomes 𝑓: 0.80 (438433 hom.)
• Consequence: SLCO1B3 NM_019844.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.497
• Publications: 3 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=-0.87).
• BP6: Variant 12-20875159-T-C is Benign according to our data. Variant chr12-20875159-T-C is described in ClinVar as Benign. ClinVar VariationId is 1225845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B3	NM_019844.4	c.728-76T>C		intron_variant	Intron 8 of 15	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.728-76T>C		intron_variant	Intron 6 of 15		NP_001358026.1
SLCO1B3	NM_001349920.2	c.644-76T>C		intron_variant	Intron 6 of 13		NP_001336849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.728-76T>C		intron_variant	Intron 8 of 15	2	NM_019844.4	ENSP00000370956.4
SLCO1B3-SLCO1B7	ENST00000540229.1	c.728-76T>C		intron_variant	Intron 6 of 15	2		ENSP00000441269.1

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100550 AN: 151932 Hom.: 36476 Cov.: 31

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.866

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.714

GnomAD4 exome AF: 0.797 AC: 1083801 AN: 1359198 Hom.: 438433 AF XY: 0.801 AC XY: 544855 AN XY: 680558

African (AFR) AF: 0.332 AC: 9962 AN: 29986

American (AMR) AF: 0.723 AC: 26792 AN: 37074

Ashkenazi Jewish (ASJ) AF: 0.869 AC: 21621 AN: 24882

East Asian (EAS) AF: 0.560 AC: 21937 AN: 39198

South Asian (SAS) AF: 0.844 AC: 67016 AN: 79398

European-Finnish (FIN) AF: 0.674 AC: 35836 AN: 53196

Middle Eastern (MID) AF: 0.815 AC: 3643 AN: 4472

European-Non Finnish (NFE) AF: 0.825 AC: 853267 AN: 1034160

Other (OTH) AF: 0.769 AC: 43727 AN: 56832

GnomAD4 genome AF: 0.661 AC: 100557 AN: 152054 Hom.: 36472 Cov.: 31 AF XY: 0.657 AC XY: 48830 AN XY: 74330

African (AFR) AF: 0.350 AC: 14501 AN: 41458

American (AMR) AF: 0.723 AC: 11042 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 3005 AN: 3470

East Asian (EAS) AF: 0.540 AC: 2791 AN: 5168

South Asian (SAS) AF: 0.834 AC: 4018 AN: 4816

European-Finnish (FIN) AF: 0.653 AC: 6908 AN: 10586

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.821 AC: 55816 AN: 67970

Other (OTH) AF: 0.712 AC: 1502 AN: 2110

Alfa AF: 0.661 Hom.: 5365

Bravo AF: 0.654

Asia WGS AF: 0.650 AC: 2259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

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	-0.87
CADD	Benign	8.6
DANN	Benign	0.32
PhyloP100		0.50
Mutation Taster		=100/0	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: rs3829311; hg19: chr12-21028093; COSMIC: COSV53938168;