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rs713993050

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000033.4(ABCD1):c.253dup(p.Arg85ProfsTer110) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F83F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 25)

Consequence

ABCD1
NM_000033.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.13
Variant links:
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 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-153725514-T-TC is Pathogenic according to our data. Variant chrX-153725514-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 162148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ABCD1NM_000033.4 linkuse as main transcriptc.253dup p.Arg85ProfsTer110 frameshift_variant 1/10 ENST00000218104.6
ABCD1XM_047441916.1 linkuse as main transcriptc.253dup p.Arg85ProfsTer110 frameshift_variant 1/11
ABCD1XM_047441917.1 linkuse as main transcriptc.253dup p.Arg85ProfsTer110 frameshift_variant 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABCD1ENST00000218104.6 linkuse as main transcriptc.253dup p.Arg85ProfsTer110 frameshift_variant 1/101 NM_000033.4 P1

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
25

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeMay 05, 2022ClinVar contains an entry for this variant (Variation ID: 162148). This premature translational stop signal has been observed in individual(s) with clinical features of X-linked adrenoleukodystrophy (PMID: 15811009, 27489563). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg85Profs*110) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedresearchFaculty of Medicine, Iran University of Medical Sciences (IUMS)Sep 17, 2014Present study is the first to report clinical and genetics characteristics of Iranian X-ALD patients, Lorestan province. It also highlighted the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities with subsequent elevated prevalence. Unexpectedly, there exist childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes of ALD in our pedigree with the same variant. X-ALD also occurred significantly more in our studied Iranian pedigree compared to its reported prevalence (Odd Ratio 4249.7500, 95% CI 224.6575 to 80390.7075, p-value< 0.0001). -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 02, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs713993050; hg19: chrX-152990969; API