rs188824058
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate
The NM_003742.4(ABCB11):c.1460G>T(p.Arg487Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,544 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487H) has been classified as Pathogenic.
Frequency
Consequence
NM_003742.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCB11 | ENST00000650372.1 | c.1460G>T | p.Arg487Leu | missense_variant | Exon 14 of 28 | NM_003742.4 | ENSP00000497931.1 | |||
ABCB11 | ENST00000439188.1 | n.8G>T | non_coding_transcript_exon_variant | Exon 1 of 15 | 2 | ENSP00000416058.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460544Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726556
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg487 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18395098, 18937870; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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) performed at Invitae indicates that this missense variant is expected to disrupt ABCB11 protein function. This variant has not been reported in the literature in individuals affected with ABCB11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 487 of the ABCB11 protein (p.Arg487Leu). -
Progressive familial intrahepatic cholestasis type 2 Uncertain:1
The p.Arg487Leu variant in ABCB11 has not been previously in the literature in individuals with BSEP deficiency, and has been identified in 0.0001% (1/91028) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1366346212). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 2070502) and has been interpreted as likely pathogenic by Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional likely pathogenic/pathogenic variants, resulting in a different amino acid change at the same position (p.Arg487Pro, p.Arg487His, p.Arg487Cys), have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 1070887, 290081, 2201969). In summary, the clinical significance of the p.Arg487Leu variant is uncertain. ACMG/AMP Criteria applied: PM5, PP3, PM2_supporting (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.