rs1557054875
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_000033.4(ABCD1):c.1780+2T>G variant causes a splice donor change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 24)
Consequence
ABCD1
NM_000033.4 splice_donor
NM_000033.4 splice_donor
Scores
3
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.83
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 16 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant X-153740721-T-G is Pathogenic according to our data. Variant chrX-153740721-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 458636.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.1780+2T>G | splice_donor_variant | ENST00000218104.6 | |||
LOC124905226 | XR_007068350.1 | n.827A>C | non_coding_transcript_exon_variant | 1/2 | |||
ABCD1 | XM_047441916.1 | c.2080+2T>G | splice_donor_variant | ||||
ABCD1 | XM_047441917.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCD1 | ENST00000218104.6 | c.1780+2T>G | splice_donor_variant | 1 | NM_000033.4 | P1 | |||
PLXNB3-AS1 | ENST00000434284.1 | n.72-2143A>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
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 | Jun 05, 2023 | ClinVar contains an entry for this variant (Variation ID: 458636). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in aberrant splicing and introduces a premature termination codon (PMID: 25835712). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant is also known as T(+2)->G. Disruption of this splice site has been observed in individual(s) with adrenoleukodystrophy (PMID: 10480364, 21889498, 25835712). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the ABCD1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at