12-20858546-T-G

Variant names:

• chr12-20858546-T-G
• rs4149117
• NM_019844.4:c.334T>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.334T>G​(p.Ser112Ala) variant causes a missense change. The variant allele was found at a frequency of 0.829 in 1,603,716 control chromosomes in the GnomAD database, including 558,931 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S112Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.72 (42477 hom., cov: 32)
  • Exomes 𝑓: 0.84 (516454 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.50
• Publications: 196 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 (MetaRNN=9.909534E-7).
• BP6: Variant 12-20858546-T-G is Benign according to our data. Variant chr12-20858546-T-G is described in ClinVar as Benign. ClinVar VariationId is 261184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019844.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	NM_019844.4	MANE Select	c.334T>G	p.Ser112Ala	missense	Exon 5 of 16	NP_062818.1
	SLCO1B3-SLCO1B7	NM_001371097.1		c.334T>G	p.Ser112Ala	missense	Exon 3 of 16	NP_001358026.1
	SLCO1B3	NM_001349920.2		c.250T>G	p.Ser84Ala	missense	Exon 3 of 14	NP_001336849.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B3	ENST00000381545.8	TSL:2 MANE Select	c.334T>G	p.Ser112Ala	missense	Exon 5 of 16	ENSP00000370956.4
	SLCO1B3-SLCO1B7	ENST00000540229.1	TSL:2	c.334T>G	p.Ser112Ala	missense	Exon 3 of 16	ENSP00000441269.1
	SLCO1B3	ENST00000261196.6	TSL:1	c.334T>G	p.Ser112Ala	missense	Exon 3 of 14	ENSP00000261196.2

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110075 AN: 151858 Hom.: 42480 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.856

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.899

Gnomad FIN AF: 0.746

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.779

GnomAD2 exomes AF: 0.808 AC: 202973 AN: 251138 AF XY: 0.823

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.802

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.724

Gnomad FIN exome AF: 0.755

Gnomad NFE exome AF: 0.854

Gnomad OTH exome AF: 0.827

GnomAD4 exome AF: 0.840 AC: 1219210 AN: 1451740 Hom.: 516454 Cov.: 36 AF XY: 0.844 AC XY: 609841 AN XY: 722982

African (AFR) AF: 0.415 AC: 13794 AN: 33248

American (AMR) AF: 0.803 AC: 35859 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 23281 AN: 26052

East Asian (EAS) AF: 0.708 AC: 27999 AN: 39538

South Asian (SAS) AF: 0.906 AC: 77966 AN: 86008

European-Finnish (FIN) AF: 0.762 AC: 40656 AN: 53384

Middle Eastern (MID) AF: 0.874 AC: 5023 AN: 5750

European-Non Finnish (NFE) AF: 0.857 AC: 945105 AN: 1103036

Other (OTH) AF: 0.825 AC: 49527 AN: 60046

GnomAD4 genome AF: 0.724 AC: 110099 AN: 151976 Hom.: 42477 Cov.: 32 AF XY: 0.723 AC XY: 53728 AN XY: 74268

African (AFR) AF: 0.435 AC: 18050 AN: 41450

American (AMR) AF: 0.812 AC: 12398 AN: 15264

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

East Asian (EAS) AF: 0.720 AC: 3711 AN: 5154

South Asian (SAS) AF: 0.900 AC: 4336 AN: 4816

European-Finnish (FIN) AF: 0.746 AC: 7871 AN: 10558

Middle Eastern (MID) AF: 0.880 AC: 257 AN: 292

European-Non Finnish (NFE) AF: 0.853 AC: 57963 AN: 67948

Other (OTH) AF: 0.779 AC: 1645 AN: 2112

Alfa AF: 0.817 Hom.: 250828

Bravo AF: 0.717

TwinsUK AF: 0.858 AC: 3180

ALSPAC AF: 0.854 AC: 3290

ESP6500AA AF: 0.448 AC: 1974

ESP6500EA AF: 0.864 AC: 7427

ExAC AF: 0.804 AC: 97647

Asia WGS AF: 0.764 AC: 2653 AN: 3476

EpiCase AF: 0.860

EpiControl AF: 0.865

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.

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2021

Genome-Nilou Lab

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

SLCO1B3-related disorder Benign:1

Dec 29, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.27
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.084	T
MetaRNN	Benign	9.9e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.7	N
PhyloP100		4.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.0069
ClinPred		0.0051	T
GERP RS		4.0
Varity_R		0.083
gMVP		0.40
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4149117; hg19: chr12-21011480; COSMIC: COSV53937987; COSMIC: COSV53937987;