chrX-153740155-C-G

Position:

• chrX-153740155-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000033.4(ABCD1):​c.1552C>G​(p.Arg518Gly) variant causes a missense change involving the alteration of a non-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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.985

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 12 ACMG points.

• PM1: In a hotspot region, there are 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153740156-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-153740155-C-G is Pathogenic according to our data. Variant chrX-153740155-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 528337.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.1552C>G	p.Arg518Gly	missense_variant	6/10	ENST00000218104.6
LOC124905226	XR_007068350.1	n.1393G>C		non_coding_transcript_exon_variant	1/2
ABCD1	XM_047441916.1	c.1852C>G	p.Arg618Gly	missense_variant	7/11
ABCD1	XM_047441917.1	c.1608C>G	p.Ser536=	synonymous_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.1552C>G	p.Arg518Gly	missense_variant	6/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1	n.72-1577G>C		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2	n.555C>G		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2017

For these reasons, this variant has been classified as Pathogenic. Different missense substitutions at this codon (p.Arg518Gln, p.Arg518Trp, p.Arg518Pro) have been reported in several individuals affected with adrenoleukodystrophy (PMID: 21068741, 20195870, 8040304, 27084228). This suggests that the arginine residue is critical for ABCD1 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in several individuals affected with adrenoleukodystrophy  (PMID: 14767898, 16415970). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 518 of the ABCD1 protein (p.Arg518Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.96		Gain of methylation at K513 (P = 0.034);
MVP		1.0
MPC		1.7
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.95
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

LitVar

Other links and lift over

dbSNP: rs128624224; hg19: chrX-153005609;