X-153736112-A-G

Variant names:

• chrX-153736112-A-G
• rs1557054156
• NM_000033.4:c.1082A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000033.4(ABCD1):​c.1082A>G​(p.Asp361Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000922 in 1,084,253 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on 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: 25)
  • Exomes 𝑓: 0.0000092 (0 hom. 2 hem.)
• Consequence: ABCD1 NM_000033.4 missense, splice_region
• Scores: Splicing: ADA: 0.002822
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28
• 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 XL,AD gene.

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.1082A>G	p.Asp361Gly	missense splice_region	Exon 3 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.1082A>G	p.Asp361Gly	missense splice_region	Exon 3 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.2556T>C		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1082A>G	p.Asp361Gly	missense splice_region	Exon 3 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.1082A>G	p.Asp361Gly	missense splice_region	Exon 3 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.1082A>G	p.Asp361Gly	missense splice_region	Exon 3 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000220 AC: 4 AN: 181632 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000497

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000922 AC: 10 AN: 1084253 Hom.: 0 Cov.: 35 AF XY: 0.00000565 AC XY: 2 AN XY: 354227

African (AFR) AF: 0.00 AC: 0 AN: 26086

American (AMR) AF: 0.00 AC: 0 AN: 34946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18968

East Asian (EAS) AF: 0.00 AC: 0 AN: 29583

South Asian (SAS) AF: 0.00 AC: 0 AN: 53967

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38338

Middle Eastern (MID) AF: 0.000250 AC: 1 AN: 4006

European-Non Finnish (NFE) AF: 0.0000108 AC: 9 AN: 833102

Other (OTH) AF: 0.00 AC: 0 AN: 45257

GnomAD4 genome Cov.: 25

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Adrenoleukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.54	N
PhyloP100		3.3
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.46
Sift	Benign	0.32	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.55
MutPred		0.37		Gain of glycosylation at S360 (P = 0.0285)
MVP		0.99
MPC		0.87
ClinPred		0.096	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.98
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0028
dbscSNV1_RF	Benign	0.032
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: rs1557054156; hg19: chrX-153001566;