chr12-20855090-A-C

Position:

• chr12-20855090-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_019844.4(SLCO1B3):​c.147A>C​(p.Lys49Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLCO1B3	NM_019844.4	c.147A>C	p.Lys49Asn	missense_variant	4/16	ENST00000381545.8
SLCO1B3-SLCO1B7	NM_001371097.1	c.147A>C	p.Lys49Asn	missense_variant	2/16
SLCO1B3	NM_001349920.2	c.63A>C	p.Lys21Asn	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.147A>C	p.Lys49Asn	missense_variant	4/16	2	NM_019844.4	P1
SLCO1B3	ENST00000261196.6	c.147A>C	p.Lys49Asn	missense_variant	2/14	1		P1
SLCO1B3	ENST00000540853.5	c.147A>C	p.Lys49Asn	missense_variant	3/8	1
SLCO1B3	ENST00000545880.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rotor syndrome Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T;T;.;.
Eigen	Benign	-0.00080
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;.;T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.6	.;L;L;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.31	T;D;D;D;D
Sift4G	Benign	0.22	T;T;T;T;D
Polyphen		0.94	.;P;P;.;.
Vest4		0.72, 0.72, 0.71
MutPred		0.60		Gain of catalytic residue at I46 (P = 0.003);Gain of catalytic residue at I46 (P = 0.003);Gain of catalytic residue at I46 (P = 0.003);Gain of catalytic residue at I46 (P = 0.003);Gain of catalytic residue at I46 (P = 0.003);
MVP		0.74
MPC		0.034, 0.046
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.90
gMVP		0.58

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: rs1865106191; hg19: chr12-21008024;