rs128624221
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000033.4(ABCD1):c.1390C>T(p.Arg464Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 24)
Consequence
ABCD1
NM_000033.4 stop_gained
NM_000033.4 stop_gained
Scores
2
1
2
Clinical Significance
Conservation
PhyloP100: 3.49
Genes affected
ABCD1 (HGNC:61): (ATP binding cassette subfamily D member 1) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-153736510-C-T is Pathogenic according to our data. Variant chrX-153736510-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153736510-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCD1 | NM_000033.4 | c.1390C>T | p.Arg464Ter | stop_gained | 4/10 | ENST00000218104.6 | |
LOC124905226 | XR_007068350.1 | n.3841G>A | non_coding_transcript_exon_variant | 2/2 | |||
ABCD1 | XM_047441916.1 | c.1390C>T | p.Arg464Ter | stop_gained | 4/11 | ||
ABCD1 | XM_047441917.1 | c.1390C>T | p.Arg464Ter | stop_gained | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.1390C>T | p.Arg464Ter | stop_gained | 4/10 | 1 | NM_000033.4 | P1 | |
PLXNB3-AS1 | ENST00000434284.1 | n.581-551G>A | intron_variant, non_coding_transcript_variant | 3 | |||||
ABCD1 | ENST00000443684.2 | n.393C>T | non_coding_transcript_exon_variant | 3/6 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jun 28, 2023 | This ABCD1 variant has been reported in multiple unrelated individuals with ABCD1 - related disorders, including as a de novo occurrence. It has also been reported in ClinVar (Variation ID 11302), but is absent from a large population dataset6. This nonsense variant results in a premature stop codon in exon 4 of 10, likely leading to nonsense-mediated decay and lack of protein production. We consider c.1390C>T in ABCD1 to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1994 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Arg464*) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 8040304, 16087056, 21700483, 23419472, 24480483). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11302). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PVS1, PM2, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 28, 2020 | The ABCD1 c.1390C>T (p.Arg464Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, this variant has been identified in at least six unrelated individuals with X-linked adrenoleukodystrophy, including five hemizygous males and one heterozygous female (Kemp et al. 2001; Pan et al. 2005; Asheuer et al. 2005; Wang et al. 2011; Horn et al. 2013). The phenotypes of the males included childhood cerebral adrenoleukodystrophy and adult-onset adrenomyeloneuropathy and the female had a phenotype of adrenomyeloneuropathy, and both maternal and de novo inheritance was observed (Pan et al. 2005; Asheuer et al. 2005; Wang et al. 2011; Horn et al. 2013). Control data are unavailable for the p.Arg464Ter variant, and it is absent from the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Arg464Ter variant is classified as pathogenic for X-linked adrenoleukodystrophy. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 13, 2023 | Criteria applied: PVS1,PS4,PS2_MOD,PM2_SUP - |
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The hemizygous p.Arg464Ter variant in ABCD1 was identified by our study in one individual with adrenoleukodystrophy. The p.Arg464Ter variant in ABCD1 has been reported in 1 individual with adrenoleukodystrophy (PMID: 8040304), and was absent from large population studies. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 11302). This nonsense variant leads to a premature termination codon at position 464, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCD1 gene is an established disease mechanism in autosomal recessive adrenoleukodystrophy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 17, 2022 | - - |
ABCD1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 13, 2023 | The ABCD1 c.1390C>T variant is predicted to result in premature protein termination (p.Arg464*). This variant has been reported to be causative for X-Linked adrenoleukodystrophy (reported as C1776T in Fanen et al. 1994. PMID: 8040304). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare and has been interpreted as pathogenic/likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/11302/). Nonsense variants in ABCD1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at