rs128624223

chrX-153740147-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000033.4(ABCD1):c.1544C>T(p.Ser515Phe) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.90

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 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-153740147-C-T is Pathogenic according to our data. Variant chrX-153740147-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11305.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.1544C>T	p.Ser515Phe	missense_variant	6/10	ENST00000218104.6
LOC124905226	XR_007068350.1	n.1401G>A		non_coding_transcript_exon_variant	1/2
ABCD1	XM_047441916.1	c.1844C>T	p.Ser615Phe	missense_variant	7/11
ABCD1	XM_047441917.1	c.1600C>T	p.Pro534Ser	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.1544C>T	p.Ser515Phe	missense_variant	6/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1	n.72-1569G>A		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2	n.547C>T		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 11305). This missense change has been observed in individual(s) with clinical features of adrenoleukodystrophy (PMID: 7876858, 24768737; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 515 of the ABCD1 protein (p.Ser515Phe). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1994	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Gain of methylation at K513 (P = 0.0514);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs128624223; hg19: chrX-153005601;