X-153736111-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000033.4(ABCD1):c.1082-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000033.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCD1 | NM_000033.4 | c.1082-1G>A | splice_acceptor_variant, intron_variant | Intron 2 of 9 | ENST00000218104.6 | NP_000024.2 | ||
ABCD1 | XM_047441916.1 | c.1082-1G>A | splice_acceptor_variant, intron_variant | Intron 2 of 10 | XP_047297872.1 | |||
ABCD1 | XM_047441917.1 | c.1082-1G>A | splice_acceptor_variant, intron_variant | Intron 2 of 7 | XP_047297873.1 | |||
LOC124905226 | XR_007068350.1 | n.4240C>T | non_coding_transcript_exon_variant | Exon 2 of 2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.1082-1G>A | splice_acceptor_variant, intron_variant | Intron 2 of 9 | 1 | NM_000033.4 | ENSP00000218104.3 | |||
PLXNB3-AS1 | ENST00000434284.1 | n.581-152C>T | intron_variant | Intron 2 of 2 | 3 | |||||
ABCD1 | ENST00000443684.2 | n.85-1G>A | splice_acceptor_variant, intron_variant | Intron 1 of 5 | 3 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 24
ClinVar
Submissions by phenotype
Adrenoleukodystrophy Pathogenic:1
This sequence change affects an acceptor splice site in intron 2 of the ABCD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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 variant has not been reported in the literature in individuals affected with ABCD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452524). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
not provided Pathogenic:1
The c.1082-1G>A variant in the ABCD1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1082-1G>A variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1082-1G>A as a likely pathogenic variant -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at