X-153736110-A-G

Variant names:

• chrX-153736110-A-G
• NM_000033.4:c.1082-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000033.4(ABCD1):​c.1082-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000287 in 1,043,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000029 (0 hom. 0 hem.)
• Consequence: ABCD1 NM_000033.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.05

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]

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.063896336 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of 6, new splice context is: ctggggctttgcggatgcAGagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153736110-A-G is Pathogenic according to our data. Variant chrX-153736110-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4063763.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1082-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 9	ENST00000218104.6	NP_000024.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1082-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 9	1	NM_000033.4	ENSP00000218104.3
PLXNB3-AS1	ENST00000434284.1	n.581-151T>C		intron_variant	Intron 2 of 2	3
ABCD1	ENST00000443684.2	n.85-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000287 AC: 3 AN: 1043714 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 336694

African (AFR) AF: 0.00 AC: 0 AN: 24903

American (AMR) AF: 0.00 AC: 0 AN: 33904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17689

East Asian (EAS) AF: 0.00 AC: 0 AN: 26224

South Asian (SAS) AF: 0.00 AC: 0 AN: 53555

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33857

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3776

European-Non Finnish (NFE) AF: 0.00000248 AC: 2 AN: 807089

Other (OTH) AF: 0.0000234 AC: 1 AN: 42717

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:1

Mar 17, 2025

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Benign	0.94
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.1
GERP RS		4.5
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: 8
DS_AL_spliceai		0.99		Position offset: 2

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

Publications

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Other links and lift over

hg19: chrX-153001564;