rs72549398
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_003742.4(ABCB11):c.3148C>T(p.Arg1050Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,609,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_003742.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000124 AC: 3AN: 241292Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 130428
GnomAD4 exome AF: 0.00000618 AC: 9AN: 1457002Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3AN XY: 724078
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1050 of the ABCB11 protein (p.Arg1050Cys). This variant is present in population databases (rs72549398, gnomAD 0.01%). This missense change has been observed in individual(s) with benign recurrent intrahepatic cholestasis (PMID: 15300568, 31015375). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374098). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB11 protein function. Studies have shown that this missense change alters ABCB11 gene expression (PMID: 17855769). For these reasons, this variant has been classified as Pathogenic. -
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Intrahepatic cholestasis;C0033774:Pruritus;C4021883:Abnormal liver function tests during pregnancy Pathogenic:1
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Benign recurrent intrahepatic cholestasis type 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at