rs797044625
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000033.4(ABCD1):c.2006_2007del(p.His669LeufsTer64) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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: 9.32
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 14 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 19 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-153743495-CCA-C is Pathogenic according to our data. Variant chrX-153743495-CCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 193546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCD1 | NM_000033.4 | c.2006_2007del | p.His669LeufsTer64 | frameshift_variant | 10/10 | ENST00000218104.6 | |
ABCD1 | XM_047441916.1 | c.2306_2307del | p.His769LeufsTer64 | frameshift_variant | 11/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.2006_2007del | p.His669LeufsTer64 | frameshift_variant | 10/10 | 1 | NM_000033.4 | P1 | |
PLXNB3-AS1 | ENST00000434284.1 | n.72-4919_72-4918del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 22, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ABCD1 protein in which other variant(s) (p.Gly678Argfs*56) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant is also known as 1999-2000delCA (H667). This premature translational stop signal has been observed in individual(s) with adrenomyeloneuropathy (PMID: 10737980). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His669Leufs*64) in the ABCD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 77 amino acid(s) of the ABCD1 protein. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 17, 2014 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at