rs387906496

Variant names:

• chrX-153726135-CGGA-C
• rs387906496
• NM_000033.4:c.874_876delGAG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000033.4(ABCD1):​c.874_876delGAG​(p.Glu292del) variant causes a conservative inframe deletion change involving the alteration of a 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: 26)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.59
• Publications: 5 publications found

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]

ABCD1 Gene-Disease associations (from GenCC):

• adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• X-linked cerebral adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary spastic paraplegia

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• adrenomyeloneuropathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000033.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-153726135-CGGA-C is Pathogenic according to our data. Variant chrX-153726135-CGGA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11314.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.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	NM_001440747.1	c.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 11		NP_001427676.1
ABCD1	XM_047441917.1	c.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000370129.4	c.319_321delGAG	p.Glu107del	conservative_inframe_deletion	Exon 1 of 2	2		ENSP00000359147.3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.51e-7 AC: 1 AN: 1050997 Hom.: 0 AF XY: 0.00000300 AC XY: 1 AN XY: 333211

African (AFR) AF: 0.00 AC: 0 AN: 25384

American (AMR) AF: 0.00 AC: 0 AN: 29221

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17435

East Asian (EAS) AF: 0.00 AC: 0 AN: 28392

South Asian (SAS) AF: 0.00 AC: 0 AN: 47508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3989

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 817799

Other (OTH) AF: 0.00 AC: 0 AN: 44185

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:3

Aug 21, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000011314 /PMID: 7668254). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 11, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 03, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs387906496; hg19: chrX-152991590;