NM_019844.4:c.1557A>G

Variant names:

• chr12-20883477-A-G
• rs2053098
• NM_019844.4:c.1557A>G

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.1557A>G​(p.Ala519Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.829 in 1,594,240 control chromosomes in the GnomAD database, including 556,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (42474 hom., cov: 32)
  • Exomes 𝑓: 0.84 (513860 hom.)
• Consequence: SLCO1B3 NM_019844.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.70
• Publications: 29 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=-1.02).
• BP6: Variant 12-20883477-A-G is Benign according to our data. Variant chr12-20883477-A-G is described in ClinVar as Benign. ClinVar VariationId is 261183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B3	NM_019844.4	c.1557A>G	p.Ala519Ala	synonymous_variant	Exon 13 of 16	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.1557A>G	p.Ala519Ala	synonymous_variant	Exon 11 of 16		NP_001358026.1
SLCO1B3	NM_001349920.2	c.1473A>G	p.Ala491Ala	synonymous_variant	Exon 11 of 14		NP_001336849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.1557A>G	p.Ala519Ala	synonymous_variant	Exon 13 of 16	2	NM_019844.4	ENSP00000370956.4
SLCO1B3-SLCO1B7	ENST00000540229.1	c.1557A>G	p.Ala519Ala	synonymous_variant	Exon 11 of 16	2		ENSP00000441269.1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110100 AN: 151922 Hom.: 42477 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.900

Gnomad FIN AF: 0.746

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.778

GnomAD2 exomes AF: 0.811 AC: 193111 AN: 238070 AF XY: 0.826

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 0.729

Gnomad FIN exome AF: 0.755

Gnomad NFE exome AF: 0.855

Gnomad OTH exome AF: 0.829

GnomAD4 exome AF: 0.840 AC: 1212001 AN: 1442200 Hom.: 513860 Cov.: 32 AF XY: 0.844 AC XY: 606036 AN XY: 718018

African (AFR) AF: 0.418 AC: 13459 AN: 32226

American (AMR) AF: 0.805 AC: 33450 AN: 41534

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 23157 AN: 25894

East Asian (EAS) AF: 0.710 AC: 27372 AN: 38546

South Asian (SAS) AF: 0.909 AC: 76018 AN: 83650

European-Finnish (FIN) AF: 0.762 AC: 40591 AN: 53292

Middle Eastern (MID) AF: 0.872 AC: 4869 AN: 5584

European-Non Finnish (NFE) AF: 0.857 AC: 943897 AN: 1101862

Other (OTH) AF: 0.825 AC: 49188 AN: 59612

GnomAD4 genome AF: 0.724 AC: 110124 AN: 152040 Hom.: 42474 Cov.: 32 AF XY: 0.723 AC XY: 53751 AN XY: 74308

African (AFR) AF: 0.436 AC: 18051 AN: 41448

American (AMR) AF: 0.811 AC: 12387 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3089 AN: 3472

East Asian (EAS) AF: 0.719 AC: 3717 AN: 5168

South Asian (SAS) AF: 0.902 AC: 4346 AN: 4820

European-Finnish (FIN) AF: 0.746 AC: 7867 AN: 10550

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

European-Non Finnish (NFE) AF: 0.853 AC: 57984 AN: 67986

Other (OTH) AF: 0.778 AC: 1646 AN: 2116

Alfa AF: 0.791 Hom.: 34613

Bravo AF: 0.717

Asia WGS AF: 0.763 AC: 2652 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:3

Jan 13, 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	-1.0
CADD	Benign	0.28
DANN	Benign	0.50
PhyloP100		-3.7
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: rs2053098; hg19: chr12-21036411; COSMIC: COSV53938181;