rs1557053262

Variant names:

• chrX-153729412-G-A
• rs1557053262
• NM_000033.4:c.1081G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-153729412-G-A
• chrX-153729412-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000033.4(ABCD1):​c.1081G>A​(p.Asp361Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. 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. D361Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ABCD1 NM_000033.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.1081G>A	p.Asp361Asn	missense splice_region	Exon 2 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.1081G>A	p.Asp361Asn	missense splice_region	Exon 2 of 11	NP_001427676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1081G>A	p.Asp361Asn	missense splice_region	Exon 2 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000370129.4	TSL:2	c.526G>A	p.Gly176Ser	missense	Exon 2 of 2	ENSP00000359147.3	A6NEP8
	ABCD1	ENST00000862307.1		c.1081G>A	p.Asp361Asn	missense splice_region	Exon 2 of 11	ENSP00000532366.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Benign	0.91
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.93	L
PhyloP100		9.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.36
Sift	Benign	0.18	T
Sift4G	Benign	0.30	T
Polyphen		0.0020	B
Vest4		0.49
MutPred		0.29		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.97
MPC		0.85
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.96
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: 0

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

Other links and lift over

dbSNP: rs1557053262; hg19: chrX-152994867;