NM_000033.4:c.488G>C

Variant names:

• chrX-153725754-G-C
• rs1057517954
• NM_000033.4:c.488G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000033.4(ABCD1):​c.488G>C​(p.Arg163Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 26)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.54
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• X-linked cerebral adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary spastic paraplegia

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• adrenomyeloneuropathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 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-153725753-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1323835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-153725754-G-C is Pathogenic according to our data. Variant chrX-153725754-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2630273.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.488G>C	p.Arg163Pro	missense_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	NM_001440747.1	c.488G>C	p.Arg163Pro	missense_variant	Exon 1 of 11		NP_001427676.1
ABCD1	XM_047441917.1	c.488G>C	p.Arg163Pro	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.488G>C	p.Arg163Pro	missense_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000370129.4	c.-68G>C		upstream_gene_variant		2		ENSP00000359147.3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

ABCD1-related disorder Pathogenic:1

Feb 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCD1 c.488G>C variant is predicted to result in the amino acid substitution p.Arg163Pro. This variant has been reported in multiple individuals with adrenomyeloneuropathy/adrenoleukodystrophy phenotypes (Ohi et al 2000. PubMed ID: 10980309; Matsumoto et al. 2003. PubMed ID: 12624723; Kemp et al. 2001. PubMed ID: 11748843; https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.96		Loss of MoRF binding (P = 0.0108);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		0.0062	Neutral
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1057517954; hg19: chrX-152991209;