Genetic Variant NM_019844.4:c.439A>T (chr12-20861096-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_019844.4(SLCO1B3):c.439A>T(p.Thr147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T147A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLCO1B3
NM_019844.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.999

Publications

11 publications found

Variant links:

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 links:

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]

SLCO1B3-SLCO1B7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03465557).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019844.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLCO1B3	NM_019844.4	MANE Select	c.439A>T	p.Thr147Ser	missense	Exon 6 of 16	NP_062818.1	Q9NPD5-1
SLCO1B3-SLCO1B7	NM_001371097.1		c.439A>T	p.Thr147Ser	missense	Exon 4 of 16	NP_001358026.1	A0A0A6YYJ9
SLCO1B3	NM_001349920.2		c.355A>T	p.Thr119Ser	missense	Exon 4 of 14	NP_001336849.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLCO1B3	ENST00000381545.8	TSL:2 MANE Select	c.439A>T	p.Thr147Ser	missense	Exon 6 of 16	ENSP00000370956.4	Q9NPD5-1
SLCO1B3-SLCO1B7	ENST00000540229.1	TSL:2	c.439A>T	p.Thr147Ser	missense	Exon 4 of 16	ENSP00000441269.1
SLCO1B3	ENST00000261196.6	TSL:1	c.439A>T	p.Thr147Ser	missense	Exon 4 of 14	ENSP00000261196.2	Q9NPD5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450360

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33008

American (AMR)

AF:

0.00

AC:

AN:

43030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39356

South Asian (SAS)

AF:

0.00

AC:

AN:

83950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106032

Other (OTH)

AF:

0.00

AC:

AN:

60008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

3.7

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.055

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.11

M_CAP

Benign

0.0020

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

PhyloP100

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

REVEL

Benign

0.063

Sift

Benign

0.96

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.16

MutPred

0.39

Gain of catalytic residue at L143 (P = 0)

MVP

0.12

MPC

0.0069

ClinPred

0.076

GERP RS

1.1

Varity_R

0.051

gMVP

0.12

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over