12-20855051-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019844.4(SLCO1B3):c.108C>G(p.Phe36Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,611,122 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (6 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0330

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004777491).
• BP6: Variant 12-20855051-C-G is Benign according to our data. Variant chr12-20855051-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 307885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00551 (839/152220) while in subpopulation AFR AF= 0.0197 (820/41536). AF 95% confidence interval is 0.0186. There are 13 homozygotes in gnomad4. There are 418 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLCO1B3	NM_019844.4	c.108C>G	p.Phe36Leu	missense_variant	4/16	ENST00000381545.8
SLCO1B3-SLCO1B7	NM_001371097.1	c.108C>G	p.Phe36Leu	missense_variant	2/16
SLCO1B3	NM_001349920.2	c.24C>G	p.Phe8Leu	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.108C>G	p.Phe36Leu	missense_variant	4/16	2	NM_019844.4	P1
SLCO1B3	ENST00000261196.6	c.108C>G	p.Phe36Leu	missense_variant	2/14	1		P1
SLCO1B3	ENST00000540853.5	c.108C>G	p.Phe36Leu	missense_variant	3/8	1
SLCO1B3	ENST00000545880.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00552 AC: 839 AN: 152102 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00149 AC: 373 AN: 249912 Hom.: 4 AF XY: 0.00104 AC XY: 140 AN XY: 135088

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.000938

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000605 AC: 882 AN: 1458902 Hom.: 6 Cov.: 30 AF XY: 0.000522 AC XY: 379 AN XY: 725710

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.000902

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00551 AC: 839 AN: 152220 Hom.: 13 Cov.: 32 AF XY: 0.00562 AC XY: 418 AN XY: 74402

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.00612

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0213 AC: 94

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00180 AC: 219

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

SLCO1B3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	8.6
Dann	Benign	0.88
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.52	T;.;T;T;T
MetaRNN	Benign	0.0048	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Benign	0.058
Sift	Benign	0.14	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.078	.;B;B;.;.
Vest4		0.28, 0.28, 0.26, 0.29
MutPred		0.54		Gain of catalytic residue at S35 (P = 2e-04);Gain of catalytic residue at S35 (P = 2e-04);Gain of catalytic residue at S35 (P = 2e-04);Gain of catalytic residue at S35 (P = 2e-04);Gain of catalytic residue at S35 (P = 2e-04);
MVP		0.17
MPC		0.0071, 0.0085
ClinPred		0.022	T
GERP RS		1.9
Varity_R		0.34
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79042365; hg19: chr12-21007985;