X-153725248-GGCAGCCAGCCCAGGTGACATGCCGGT-G

Position:

• chrX-153725248-GGCAGCCAGCCCAGGTGACATGCCGGT-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000033.4(ABCD1):​c.-16_10del variant causes a start lost, 5 prime UTR 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 (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: ABCD1 NM_000033.4 start_lost, 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.78

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153725248-GGCAGCCAGCCCAGGTGACATGCCGGT-G is Pathogenic according to our data. Variant chrX-153725248-GGCAGCCAGCCCAGGTGACATGCCGGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 11317.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.-16_10del		start_lost, 5_prime_UTR_variant	1/10	ENST00000218104.6
ABCD1	XM_047441916.1	c.-16_10del		start_lost, 5_prime_UTR_variant	1/11
ABCD1	XM_047441917.1	c.-16_10del		start_lost, 5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.-16_10del		start_lost, 5_prime_UTR_variant	1/10	1	NM_000033.4	P1

Frequencies

GnomAD3 genomes Cov.: 25

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 11, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 14, 2021	This sequence change affects the initiator methionine of the ABCD1 mRNA. The next in-frame methionine is located at codon 67. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. Disruption of the initiator codon has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 11739809, 18306728). It has also been observed to segregate with disease in related individuals. This variant is also known as _x0006_delta26, 369–394 deletion. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906497; hg19: chrX-152990703;