rs375315619
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP2PP5BP4
The NM_000443.4(ABCB4):c.1529A>G(p.Asn510Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,614,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. N510D) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCB4 | NM_000443.4 | c.1529A>G | p.Asn510Ser | missense_variant | 13/28 | ENST00000649586.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCB4 | ENST00000649586.2 | c.1529A>G | p.Asn510Ser | missense_variant | 13/28 | NM_000443.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152240Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000199 AC: 50AN: 251250Hom.: 1 AF XY: 0.000265 AC XY: 36AN XY: 135824
GnomAD4 exome AF: 0.000200 AC: 292AN: 1461832Hom.: 1 Cov.: 33 AF XY: 0.000237 AC XY: 172AN XY: 727214
GnomAD4 genome AF: 0.000125 AC: 19AN: 152358Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74510
ClinVar
Submissions by phenotype
not provided Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | ABCB4: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 17, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 08, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 510 of the ABCB4 protein (p.Asn510Ser). This variant is present in population databases (rs375315619, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with autosomal recessive progressive familial intrahepatic cholestasis type 3 and/or intrahepatic cholestasis of pregnancy (PMID: 23022423, 23533021, 26324191, 26474921, 28776642, 32581362, 32917322, 34376370). ClinVar contains an entry for this variant (Variation ID: 291252). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26474921). 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. - |
Uncertain significance, flagged submission | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 25, 2016 | - - |
Cholestasis, intrahepatic, of pregnancy, 3 Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 12, 2023 | - - |
Progressive familial intrahepatic cholestasis type 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 12, 2023 | - - |
ABCB4-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 12, 2024 | The ABCB4 c.1529A>G variant is predicted to result in the amino acid substitution p.Asn510Ser. In the heterozygous state alone, this variant was reported in patients with intrahepatic cholestasis of pregnancy (ICP) (Anzivino. 2013. PubMed ID: 23022423; Poupon. 2013. PubMed ID: 23533021; Falcão. 2021. PubMed ID: 34376370; Stalke 2017. PubMed ID: 28776642). In the compound heterozygous state with another pathogenic ABCB4 variant, this variant was reported to cause progressive familial intrahepatic cholestasis (PFIC) (Delaunay. 2015. PubMed ID: 26474921; Davit-Spraul. 2010. PubMed ID: 20422496; Falcão. 2021. PubMed ID: 34376370). Functional assays in the Delaunay study indicated the p.Asn510Ser change reduced protein stability. This variant is reported in 0.062% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. - |
Progressive familial intrahepatic cholestasis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: ABCB4 c.1529A>G (p.Asn510Ser) results in a conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251250 control chromosomes, predominantly at a frequency of 0.00062 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.0022), allowing no conclusion about variant significance. The variant, c.1529A>G, has been reported in the literature in (presumed) compound heterozygous state together with a second (likely) pathogenic variant in individuals affected with hepatobiliary disease and intrahepatic cholestasis of pregnancy (e.g. Delaunay_2016, Stalke_2018, Falcao_2022). The variant has been also reported in (apparent) heterozygosity in affected individuals in whom a second (likely) pathogenic mutation was not identified. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated decreased protein stability (Delaunay_2016). The following publications have been ascertained in the context of this evaluation (PMID: 32917322, 26324191, 26474921, 28587926, 32626542, 28776642, 19467940, 34376370). Eight other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant with conflicting assessments, i.e. as pathogenic (n=3), likely pathogenic (n=4), or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Progressive familial intrahepatic cholestasis type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Severe early-childhood-onset retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at