rs398123108

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000033.4(ABCD1):c.1866-10G>A variant causes a 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
NM_000033.4 intron

Scores

Splicing: ADA: 0.9973

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: -1.21

Publications

3 publications found

Variant links:

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]

ABCD1 links:

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

PLXNB3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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 rank	MANE	Protein	UniProt
ABCD1	NM_000033.4 link	c.1866-10G>A		intron_variant	Intron 8 of 9	ENST00000218104.6	NP_000024.2	P33897

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6 link	c.1866-10G>A		intron_variant	Intron 8 of 9	1	NM_000033.4	ENSP00000218104.3		P33897
PLXNB3-AS1	ENST00000434284.1 link	n.72-4633C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1093390

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360508

African (AFR)

AF:

0.00

AC:

AN:

26300

American (AMR)

AF:

0.00

AC:

AN:

34933

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19289

East Asian (EAS)

AF:

0.00

AC:

AN:

30095

South Asian (SAS)

AF:

0.00

AC:

AN:

53297

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39935

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2951

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840788

Other (OTH)

AF:

0.00

AC:

AN:

45802

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Pathogenic:6

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of adrenoleukodystrophy (PMID: 8535452, 21966424, 31104286). ClinVar contains an entry for this variant (Variation ID: 92323). Studies have shown that this variant alters ABCD1 gene expression (PMID: 21966424). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 13, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Nov 07, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 26, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 14, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 14, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

-1.2

Mutation Taster

=33/67

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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