X-153736113-T-A

Variant names:

• chrX-153736113-T-A
• rs201973942
• NM_000033.4:c.1083T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000033.4(ABCD1):​c.1083T>A​(p.Asp361Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D361Y) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
• Consequence: ABCD1 NM_000033.4 missense, splice_region
• Scores: Splicing: ADA: 0.001976
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.943

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]

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a domain ABC transmembrane type-1 (size 292) in uniprot entity ABCD1_HUMAN there are 192 pathogenic changes around while only 41 benign (82%) in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08217603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1083T>A	p.Asp361Glu	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000218104.6	NP_000024.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1083T>A	p.Asp361Glu	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000443684.2	n.86T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 6	3
PLXNB3-AS1	ENST00000434284.1	n.581-154A>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111748 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000938

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181628 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111798 Hom.: 0 Cov.: 24 AF XY: 0.0000293 AC XY: 1 AN XY: 34136

African (AFR) AF: 0.00 AC: 0 AN: 30806

American (AMR) AF: 0.0000936 AC: 1 AN: 10680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3513

South Asian (SAS) AF: 0.00 AC: 0 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53004

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L
PhyloP100		0.94
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.35
Sift	Benign	0.51	T
Sift4G	Benign	0.58	T
Polyphen		0.18	B
Vest4		0.33
MutPred		0.28		Loss of loop (P = 0.0804);
MVP		0.95
MPC		0.53
ClinPred		0.056	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.94
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0020
dbscSNV1_RF	Benign	0.076
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs201973942; hg19: chrX-153001567;