rs60140950

Positions:

• chr12-20875274-G-A
• chr12-20875274-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_019844.4(SLCO1B3):​c.767G>A​(p.Gly256Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SLCO1B3 NM_019844.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLCO1B3	NM_019844.4	c.767G>A	p.Gly256Glu	missense_variant	9/16	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.767G>A	p.Gly256Glu	missense_variant	7/16		NP_001358026.1
SLCO1B3	NM_001349920.2	c.683G>A	p.Gly228Glu	missense_variant	7/14		NP_001336849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.767G>A	p.Gly256Glu	missense_variant	9/16	2	NM_019844.4	ENSP00000370956	P1
SLCO1B3	ENST00000261196.6	c.767G>A	p.Gly256Glu	missense_variant	7/14	1		ENSP00000261196	P1
SLCO1B3	ENST00000540853.5	c.767G>A	p.Gly256Glu	missense_variant	8/8	1		ENSP00000442000
SLCO1B3	ENST00000544370.1	c.239G>A	p.Gly80Glu	missense_variant	3/10	5		ENSP00000443225

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461060 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	4.2	.;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.5	D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.95, 0.95, 0.94
MutPred		0.65		Gain of catalytic residue at W258 (P = 0);Gain of catalytic residue at W258 (P = 0);Gain of catalytic residue at W258 (P = 0);.;Gain of catalytic residue at W258 (P = 0);
MVP		0.54
MPC		0.033, 0.045
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.97
gMVP		0.88

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: rs60140950; hg19: chr12-21028208; COSMIC: COSV105034342;