12-20855097-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_019844.4(SLCO1B3):c.154A>G(p.Ile52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,612,072 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (3 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.90

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013580769).
• BP6: Variant 12-20855097-A-G is Benign according to our data. Variant chr12-20855097-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377085.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLCO1B3	NM_019844.4	c.154A>G	p.Ile52Val	missense_variant	4/16	ENST00000381545.8
SLCO1B3-SLCO1B7	NM_001371097.1	c.154A>G	p.Ile52Val	missense_variant	2/16
SLCO1B3	NM_001349920.2	c.70A>G	p.Ile24Val	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.154A>G	p.Ile52Val	missense_variant	4/16	2	NM_019844.4	P1
SLCO1B3	ENST00000261196.6	c.154A>G	p.Ile52Val	missense_variant	2/14	1		P1
SLCO1B3	ENST00000540853.5	c.154A>G	p.Ile52Val	missense_variant	3/8	1
SLCO1B3	ENST00000545880.1	n.6A>G		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.00

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000558 AC: 140 AN: 250900 Hom.: 0 AF XY: 0.000428 AC XY: 58 AN XY: 135622

Gnomad AFR exome AF: 0.00839

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1459756 Hom.: 3 Cov.: 30 AF XY: 0.000178 AC XY: 129 AN XY: 726256

Gnomad4 AFR exome AF: 0.00778

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.00228 AC: 348 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74468

Gnomad4 AFR AF: 0.00801

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000397 Hom.: 1

Bravo AF: 0.00266

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000766 AC: 93

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rotor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 11, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Oct 11, 2016

- -

SLCO1B3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2022

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	Benign	0.090
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	0.079
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;.;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.82	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.063	T;D;D;D;D
Sift4G	Benign	0.063	T;T;T;T;T
Polyphen		0.37	.;B;B;.;.
Vest4		0.39, 0.40, 0.40, 0.31
MVP		0.22
MPC		0.012, 0.011
ClinPred		0.065	T
GERP RS		3.8
Varity_R		0.18
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs57325543; hg19: chr12-21008031;