NM_000033.4:c.1780+2T>G

Variant names:

• chrX-153740721-T-G
• rs1557054875
• NM_000033.4:c.1780+2T>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.1780+2T>G variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ABCD1 NM_000033.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.83

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]

LOC124905226 (HGNC:):

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

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153740721-T-G is Pathogenic according to our data. Variant chrX-153740721-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 458636.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1780+2T>G		splice_donor_variant, intron_variant	Intron 7 of 9	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.2080+2T>G		splice_donor_variant, intron_variant	Intron 8 of 10		XP_047297872.1
LOC124905226	XR_007068350.1	n.827A>C		non_coding_transcript_exon_variant	Exon 1 of 2
ABCD1	XM_047441917.1	c.*110T>G		downstream_gene_variant			XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1780+2T>G		splice_donor_variant, intron_variant	Intron 7 of 9	1	NM_000033.4	ENSP00000218104.3
PLXNB3-AS1	ENST00000434284.1	n.72-2143A>C		intron_variant	Intron 1 of 2	3
ABCD1	ENST00000443684.2	n.*117T>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:1

Jun 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disruption of this splice site has been observed in individual(s) with adrenoleukodystrophy (PMID: 10480364, 21889498, 25835712). In at least one individual the variant was observed to be de novo. This sequence change affects a donor splice site in intron 7 of the ABCD1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant is also known as T(+2)->G. ClinVar contains an entry for this variant (Variation ID: 458636). Studies have shown that disruption of this splice site results in aberrant splicing and introduces a premature termination codon (PMID: 25835712). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557054875; hg19: chrX-153006175; COSMIC: COSV99497660; COSMIC: COSV99497660;