rs1557054176

Positions:

• chrX-153736213-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000218104.6(ABCD1):​c.1183G>C​(p.Ala395Pro) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A395V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ABCD1 ENST00000218104.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.39

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 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in ENST00000218104.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1183G>C	p.Ala395Pro	missense_variant	3/10	ENST00000218104.6	NP_000024.2
LOC124905226	XR_007068350.1	n.4138C>G		non_coding_transcript_exon_variant	2/2
ABCD1	XM_047441916.1	c.1183G>C	p.Ala395Pro	missense_variant	3/11		XP_047297872.1
ABCD1	XM_047441917.1	c.1183G>C	p.Ala395Pro	missense_variant	3/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1183G>C	p.Ala395Pro	missense_variant	3/10	1	NM_000033.4	ENSP00000218104	P1
PLXNB3-AS1	ENST00000434284.1	n.581-254C>G		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2	n.186G>C		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 446779). This variant has not been reported in the literature in individuals affected with ABCD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 395 of the ABCD1 protein (p.Ala395Pro). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.11	T
Polyphen		0.95	P
Vest4		0.89
MutPred		0.70		Loss of MoRF binding (P = 0.0707);
MVP		1.0
MPC		1.4
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.72
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1557054176; hg19: chrX-153001667;