X-153743211-G-A

Position:

• chrX-153743211-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000218104.6(ABCD1):​c.1866-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 ENST00000218104.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: -1.21

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153743211-G-A is Pathogenic according to our data. Variant chrX-153743211-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1866-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.2166-10G>A		splice_polypyrimidine_tract_variant, intron_variant			XP_047297872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1866-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000033.4	ENSP00000218104	P1
PLXNB3-AS1	ENST00000434284.1	n.72-4633C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1093390 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 360508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that this variant alters ABCD1 gene expression (PMID: 21966424). ClinVar contains an entry for this variant (Variation ID: 92323). This variant has been observed in individual(s) with clinical features of adrenoleukodystrophy (PMID: 8535452, 21966424, 31104286). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the ABCD1 gene. It does not directly change the encoded amino acid sequence of the ABCD1 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 13, 2019	This ABCD1 variant has been reported in numerous patients with phenotypes ranging from childhood cerebral adrenoleukodystrophy to adrenomyeloneuropathy. A functional study has confirmed that this variant produces a novel splice acceptor site that adds 8 nucleotides to exon 9 and destroys the native acceptor site. ABCD1 c.1866-10G>A is absent from large population datasets. Four submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. We consider this variant to be pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2024	Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26454440, 9242200, 9846054, 8004093, 22479560, 28481932, 8535452, 21966424, 31104286, 22795299, 34826210, 34946879) -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 14, 2018

The ABCD1 c.1866-10G>A variant (rs398123108), is reported in the literature in multiple individuals affected with X-linked adrenoleukodystrophy (Chen 2017, Chu 2015, Kemp 1995, Kumar 2011, Pereira Fdos 2012, ALD Mutation Database). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 92323), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant creates a novel cryptic splice site that is predicted to be the preferred acceptor site for splicing intron 8. This prediction is supported by studies showing an insertion of 8 nucleotides at the beginning of exon 9, resulting in a premature stop codon and a significant reduction in protein production (Kemp 1995, Kumar 2011). Based on available information, the c.1866-10G>A variant is considered to be pathogenic. References: Link to ALD Mutation Database: https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 Chen YH et al. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia. PLoS One. 2017 May 8;12(5):e0177296. Chu SS et al. Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy. World J Pediatr. 2015 Nov;11(4):366-73. Kemp S et al. Two intronic mutations in the adrenoleukodystrophy gene. Hum Mutat. 1995;6(3):272-3. Kumar N et al. Genomic profiling identifies novel mutations and SNPs in ABCD1 gene: a molecular, biochemical and clinical analysis of X-ALD cases in India. PLoS One. 2011;6(9):e25094. Pereira Fdos S et al. Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy. PLoS One. 2012;7(3):e34195. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2017

The c.1866-10G>A intronic pathogenic mutation results from a G to A substitution 10 nucleotides upstream from coding exon 9 in the ABCD1 gene. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site; however, direct evidence is unavailable. This mutation has been reported in several unrelated X-linked adrenoleukodystrophy (ALD) families with phenotypes ranging from adrenomyeloneuropathy to childhood-onset cerebral ALD (Kemp S et al. Hum. Mutat., 1995;6:272-3; Kumar N et al. PLoS ONE, 2011 Sep;6:e25094; Pereira Fdos S et al. PLoS ONE, 2012 Mar;7:e34195; Chu SS et al. World J Pediatr, 2015 Nov;11:366-73; Chen YH et al. PLoS ONE, 2017 May;12:e0177296). In one study, there was no detectable ALDP protein in a male with childhood cerebral ALD, whereas very low levels of protein were detected in a male with adolescent cerebral ALD (Kumar N et al. PLoS ONE, 2011 Sep;6:e25094). Analysis of the mutant transcripts from one affected male showed that this mutation activates a cryptic acceptor site causing the insertion of 8 nucleotides and a translational frameshift with a predicted alternate stop codon (p.Pro623Thrfs*16) (Kemp S et al. Hum. Mutat., 1995;6:272-3). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Spastic paraplegia;C0231687:Spastic gait Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	22
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2
DS_AL_spliceai		0.44		Position offset: 10

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123108; hg19: chrX-153008665;