rs1557055392
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000033.4(ABCD1):c.1998_1999insGC(p.His667AlafsTer25) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
ABCD1
NM_000033.4 frameshift
NM_000033.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.04
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 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-153743494-A-ACG is Pathogenic according to our data. Variant chrX-153743494-A-ACG is described in ClinVar as [Pathogenic]. Clinvar id is 458638.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCD1 | NM_000033.4 | c.1998_1999insGC | p.His667AlafsTer25 | frameshift_variant | 10/10 | ENST00000218104.6 | |
ABCD1 | XM_047441916.1 | c.2298_2299insGC | p.His767AlafsTer25 | frameshift_variant | 11/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.1998_1999insGC | p.His667AlafsTer25 | frameshift_variant | 10/10 | 1 | NM_000033.4 | P1 | |
PLXNB3-AS1 | ENST00000434284.1 | n.72-4917_72-4916insCG | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 37
GnomAD4 exome
Cov.:
37
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change creates a premature translational stop signal (p.His667Alafs*25) in the ABCD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the ABCD1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ABCD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 458638). This variant disrupts a region of the ABCD1 protein in which other variant(s) (p.Trp679*) have been determined to be pathogenic (PMID: 11748843). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at