rs147577035
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_000443.4(ABCB4):c.3764C>T(p.Thr1255Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,614,060 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 Uncertain significance (★★).
Frequency
Consequence
NM_000443.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251396Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135870
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461780Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16AN XY: 727186
GnomAD4 genome AF: 0.000151 AC: 23AN: 152280Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74446
ClinVar
Submissions by phenotype
not provided Uncertain:3
The ABCB4 p.Thr1255Met variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs147577035) and was also found in control databases in 16 of 282790 chromosomes at a frequency of 0.000057 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 12 of 24968 chromosomes (freq: 0.000481), Latino in 2 of 35440 chromosomes (freq: 0.000056), South Asian in 1 of 30616 chromosomes (freq: 0.000033) and European (non-Finnish) in 1 of 129108 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Thr1255 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1255 of the ABCB4 protein (p.Thr1255Met). This variant is present in population databases (rs147577035, gnomAD 0.05%). This missense change has been observed in individual(s) with ABCB4-related conditions (PMID: 35894240). This variant is also known as c.3785C>T (p.Thr1262Met). ClinVar contains an entry for this variant (Variation ID: 1049446). 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 ABCB4 protein function. 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. -
PM2 -
ABCB4-related disorder Uncertain:1
The ABCB4 c.3764C>T variant is predicted to result in the amino acid substitution p.Thr1255Met. This variant, also known as c.3785C>T (p.Thr1262Met), was reported in the compound heterozygous state in an individual with adult-onset liver disease (Nayagam et al 2022. PubMed ID: 35894240 Table S1). This variant is reported in 0.048% 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at