X-153742986-G-T

Variant names:

• chrX-153742986-G-T
• rs797044781
• NM_000033.4:c.1781-1G>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000033.4(ABCD1):​c.1781-1G>T variant causes a splice acceptor, 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005840570: Disruption of this splice site has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID:36256460).".

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• Publications: 0 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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 22 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005840570: Disruption of this splice site has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 36256460).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153742986-G-T is Pathogenic according to our data. Variant chrX-153742986-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2690501.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.1781-1G>T		splice_acceptor intron	N/A	NP_000024.2
	ABCD1	NM_001440747.1		c.2081-1G>T		splice_acceptor intron	N/A	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-4408C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1781-1G>T		splice_acceptor intron	N/A	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.2081-1G>T		splice_acceptor intron	N/A	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.2051-1G>T		splice_acceptor intron	N/A	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1080515 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352885

African (AFR) AF: 0.00 AC: 0 AN: 26138

American (AMR) AF: 0.00 AC: 0 AN: 33060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18904

East Asian (EAS) AF: 0.00 AC: 0 AN: 29714

South Asian (SAS) AF: 0.00 AC: 0 AN: 52025

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39207

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2877

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833293

Other (OTH) AF: 0.00 AC: 0 AN: 45297

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 9
DS_AL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs797044781; hg19: chrX-153008440;