chrX-153725284-G-GC

Variant names:

• chrX-153725284-G-GC
• NM_000033.4:c.22dupC

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.22dupC​(p.Arg8ProfsTer187) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: ABCD1 NM_000033.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.338

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 71 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153725284-G-GC is Pathogenic according to our data. Variant chrX-153725284-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2572606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.22dupC	p.Arg8ProfsTer187	frameshift_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.22dupC	p.Arg8ProfsTer187	frameshift_variant	Exon 1 of 11		XP_047297872.1
ABCD1	XM_047441917.1	c.22dupC	p.Arg8ProfsTer187	frameshift_variant	Exon 1 of 8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.22dupC	p.Arg8ProfsTer187	frameshift_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 25

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:2

Apr 24, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2 -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift variant c.22dup (p.Arg8ProfsTer187) in the ABCD1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is absent in the gnomAD Exomes. This variant causes a frameshift starting with codon Arginine 8, changes this amino acid to Proline residue, and creates a premature Stop codon at position 187 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Mehrpour et al., 2016). For these reasons, this variant has been classified as Likely Pathogenic. The same variant in the ABCD1 gene has been detected in the previous child in hemizygous state (Test done outside). -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-152990739;