chr12-20855091-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019844.4(SLCO1B3):ā€‹c.148A>Gā€‹(p.Ile50Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,459,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000062 ( 0 hom. )

Consequence

SLCO1B3
NM_019844.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.41
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18467948).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLCO1B3NM_019844.4 linkuse as main transcriptc.148A>G p.Ile50Val missense_variant 4/16 ENST00000381545.8
SLCO1B3-SLCO1B7NM_001371097.1 linkuse as main transcriptc.148A>G p.Ile50Val missense_variant 2/16
SLCO1B3NM_001349920.2 linkuse as main transcriptc.64A>G p.Ile22Val missense_variant 2/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLCO1B3ENST00000381545.8 linkuse as main transcriptc.148A>G p.Ile50Val missense_variant 4/162 NM_019844.4 P1Q9NPD5-1
SLCO1B3ENST00000261196.6 linkuse as main transcriptc.148A>G p.Ile50Val missense_variant 2/141 P1Q9NPD5-1
SLCO1B3ENST00000540853.5 linkuse as main transcriptc.148A>G p.Ile50Val missense_variant 3/81
SLCO1B3ENST00000545880.1 linkuse as main transcript upstream_gene_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250986
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135666
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000981
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000617
AC:
9
AN:
1459700
Hom.:
0
Cov.:
30
AF XY:
0.00000689
AC XY:
5
AN XY:
726214
show subpopulations
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:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Rotor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
Benign
0.083
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.074
.;T;T;.;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.20
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.53
T;.;T;T;T
M_CAP
Benign
0.0069
T
MetaRNN
Benign
0.18
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.32
.;N;N;.;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
0.13
N;N;N;N;N
REVEL
Benign
0.12
Sift
Uncertain
0.0020
D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
0.0
.;B;B;.;.
Vest4
0.12, 0.12, 0.16, 0.13
MutPred
0.61
Gain of catalytic residue at K49 (P = 0);Gain of catalytic residue at K49 (P = 0);Gain of catalytic residue at K49 (P = 0);Gain of catalytic residue at K49 (P = 0);Gain of catalytic residue at K49 (P = 0);
MVP
0.22
MPC
0.0073, 0.0093
ClinPred
0.20
T
GERP RS
3.8
Varity_R
0.22
gMVP
0.28

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs761530247; hg19: chr12-21008025; API