rs128624217

Variant names:

• chrX-153725786-T-C
• NM_000033.4:c.520T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-153725786-T-C
• chrX-153725786-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000033.4(ABCD1):​c.520T>C​(p.Tyr174His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.89

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-153725786-T-C is Pathogenic according to our data. Variant chrX-153725786-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2737405.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.520T>C	p.Tyr174His	missense_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.520T>C	p.Tyr174His	missense_variant	Exon 1 of 11		XP_047297872.1
ABCD1	XM_047441917.1	c.520T>C	p.Tyr174His	missense_variant	Exon 1 of 8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.520T>C	p.Tyr174His	missense_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000370129.4	c.-36T>C		upstream_gene_variant		2		ENSP00000359147.3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 26

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:1

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 174 of the ABCD1 protein (p.Tyr174His). This variant has not been reported in the literature in individuals affected with ABCD1-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr174 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7860075, 15811009, 21907609, 28456143). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCD1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.93		Gain of helix (P = 0.0349);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-152991241;