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]

BCAP31 (HGNC:16695): (B cell receptor associated protein 31) This gene encodes a member of the B-cell receptor associated protein 31 superfamily. The encoded protein is a multi-pass transmembrane protein of the endoplasmic reticulum that is involved in the anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi and in caspase 8-mediated apoptosis. Microdeletions in this gene are associated with contiguous ABCD1/DXS1375E deletion syndrome (CADDS), a neonatal disorder. Alternative splicing of this gene results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 16. [provided by RefSeq, Jan 2012]

BCAP31 Gene-Disease associations (from GenCC):

• severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

  Inheritance: AR, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 11314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.874_876delGAG	p.Glu292del	conservative_inframe_deletion	Exon 1 of 11	ENSP00000532365.1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Adrenoleukodystrophy (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;