rs142794414
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM2PP2BP4_Strong
The NM_000443.4(ABCB4):c.101C>T(p.Thr34Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,608,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T34K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000443.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCB4 | NM_000443.4 | c.101C>T | p.Thr34Met | missense_variant | 3/28 | ENST00000649586.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCB4 | ENST00000649586.2 | c.101C>T | p.Thr34Met | missense_variant | 3/28 | NM_000443.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00121 AC: 184AN: 151912Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000483 AC: 121AN: 250774Hom.: 0 AF XY: 0.000325 AC XY: 44AN XY: 135512
GnomAD4 exome AF: 0.000228 AC: 332AN: 1456094Hom.: 0 Cov.: 29 AF XY: 0.000232 AC XY: 168AN XY: 724850
GnomAD4 genome ? AF: 0.00123 AC: 187AN: 152030Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95AN XY: 74314
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 15, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 24, 2023 | BS1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 21, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 34 of the ABCB4 protein (p.Thr34Met). This variant is present in population databases (rs142794414, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of progressive familial intrahepatic cholestasis or low phospholipid associated cholelithiasis syndrome (PMID: 22331132, 24723470, 28355206). ClinVar contains an entry for this variant (Variation ID: 196273). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects ABCB4 function (PMID: 24723470). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
ABCB4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 29, 2023 | The ABCB4 c.101C>T variant is predicted to result in the amino acid substitution p.Thr34Met. This variant has been reported in the heterozygous state in an individual with low phospholipid-associated cholelithiasis (Wendum et al. 2012. PubMed ID: 22331132, Table 2, Patient 3). In vitro functional studies indicate that this variant does not impact protein stability, expression, and apical plasma membrane localization, but decreases ABCB4-mediated phosphatidylcholine secretion activity and impairs ABCB4 phosphorylation (Gautherot et al. 2014. PubMed ID: 24723470). This variant is reported in 0.48% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cholestasis, intrahepatic, of pregnancy, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Progressive familial intrahepatic cholestasis type 3;C2609268:Low phospholipid associated cholelithiasis;C3554241:Cholestasis, intrahepatic, of pregnancy, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Progressive familial intrahepatic cholestasis type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at