rs713993050

Positions:

• chrX-153725514-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 25)
• Consequence: ABCD1 NM_000033.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.13

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]

ACMG classification

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	Protein	UniProt
ABCD1	NM_000033.4	c.253dup	p.Arg85ProfsTer110	frameshift_variant	1/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.253dup	p.Arg85ProfsTer110	frameshift_variant	1/11		XP_047297872.1
ABCD1	XM_047441917.1	c.253dup	p.Arg85ProfsTer110	frameshift_variant	1/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.253dup	p.Arg85ProfsTer110	frameshift_variant	1/10	1	NM_000033.4	ENSP00000218104	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

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 05, 2022	ClinVar 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 provided	research	Faculty of Medicine, Iran University of Medical Sciences (IUMS)	Sep 17, 2014	Present 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 submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs713993050; hg19: chrX-152990969;