rs128624214

Positions:

• chrX-153737214-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000033.4(ABCD1):​c.1451C>G​(p.Pro484Arg) 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 (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.27

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain ABC transporter (size 226) in uniprot entity ABCD1_HUMAN there are 27 pathogenic changes around while only 0 benign (100%) 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-153737214-C-G is Pathogenic according to our data. Variant chrX-153737214-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 11293.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-153737214-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1451C>G	p.Pro484Arg	missense_variant	5/10	ENST00000218104.6	NP_000024.2
LOC124905226	XR_007068350.1	n.3137G>C		non_coding_transcript_exon_variant	2/2
ABCD1	XM_047441916.1	c.1751C>G	p.Pro584Arg	missense_variant	6/11		XP_047297872.1
ABCD1	XM_047441917.1	c.1507C>G	p.Pro503Ala	missense_variant	6/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1451C>G	p.Pro484Arg	missense_variant	5/10	1	NM_000033.4	ENSP00000218104	P1
PLXNB3-AS1	ENST00000434284.1	n.580+856G>C		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2	n.454C>G		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 30, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.93		Gain of catalytic residue at P484 (P = 0.0554);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.84

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: rs128624214; hg19: chrX-153002668;