rs1557052351
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate
The NM_000033.4(ABCD1):c.415_417del(p.Leu139del) variant causes a inframe deletion 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L138L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 25)
Consequence
ABCD1
NM_000033.4 inframe_deletion
NM_000033.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.66
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 4 uncertain in NM_000033.4
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000033.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant X-153725677-GCTC-G is Pathogenic according to our data. Variant chrX-153725677-GCTC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 528335.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.415_417del | p.Leu139del | inframe_deletion | 1/10 | ENST00000218104.6 | |
ABCD1 | XM_047441916.1 | c.415_417del | p.Leu139del | inframe_deletion | 1/11 | ||
ABCD1 | XM_047441917.1 | c.415_417del | p.Leu139del | inframe_deletion | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.415_417del | p.Leu139del | inframe_deletion | 1/10 | 1 | NM_000033.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 25
GnomAD3 genomes
?
Cov.:
25
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 25
GnomAD4 genome
?
Cov.:
25
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 02, 2022 | This variant, c.415_417del, results in the deletion of 1 amino acid(s) of the ABCD1 protein (p.Leu139del), but otherwise preserves the integrity of the reading frame. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 528335). This variant has been observed in individual(s) with X-linked adrenaleukodystrophy (PMID: 21700483). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
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Calibrated prediction
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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