12-20855082-A-T

Variant names:

• chr12-20855082-A-T
• NM_019844.4:c.139A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019844.4(SLCO1B3):​c.139A>T​(p.Ile47Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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: -0.238
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069021165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B3	NM_019844.4	c.139A>T	p.Ile47Phe	missense_variant	Exon 4 of 16	ENST00000381545.8	NP_062818.1
SLCO1B3-SLCO1B7	NM_001371097.1	c.139A>T	p.Ile47Phe	missense_variant	Exon 2 of 16		NP_001358026.1
SLCO1B3	NM_001349920.2	c.55A>T	p.Ile19Phe	missense_variant	Exon 2 of 14		NP_001336849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B3	ENST00000381545.8	c.139A>T	p.Ile47Phe	missense_variant	Exon 4 of 16	2	NM_019844.4	ENSP00000370956.4
SLCO1B3-SLCO1B7	ENST00000540229.1	c.139A>T	p.Ile47Phe	missense_variant	Exon 2 of 16	2		ENSP00000441269.1

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

not provided Uncertain:1

Aug 29, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.30
DANN	Benign	0.53
DEOGEN2	Benign	0.089	.;T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.63	T;.;T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.069	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.66	.;N;N;.;.
PhyloP100		-0.24
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.079	T;T;T;T;T
Sift4G	Benign	0.089	T;T;T;T;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.30, 0.30, 0.26, 0.28
MutPred		0.55		Gain of catalytic residue at K49 (P = 2e-04);Gain of catalytic residue at K49 (P = 2e-04);Gain of catalytic residue at K49 (P = 2e-04);Gain of catalytic residue at K49 (P = 2e-04);Gain of catalytic residue at K49 (P = 2e-04);
MVP		0.088
MPC		0.0060, 0.0076
ClinPred		0.069	T
GERP RS		-0.54
Varity_R		0.084
gMVP		0.36
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

hg19: chr12-21008016;