X-153743255-G-T

Variant names:

• chrX-153743255-G-T
• rs782041940
• NM_000033.4:c.1900G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000033.4(ABCD1):​c.1900G>T​(p.Ala634Ser) 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. 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. A634T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 3 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_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

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.1900G>T	p.Ala634Ser	missense	Exon 9 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.2200G>T	p.Ala734Ser	missense	Exon 10 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-4677C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1900G>T	p.Ala634Ser	missense	Exon 9 of 10	ENSP00000218104.3	P33897
	ABCD1	ENST00000862307.1		c.2200G>T	p.Ala734Ser	missense	Exon 10 of 11	ENSP00000532366.1
	ABCD1	ENST00000862306.1		c.2170G>T	p.Ala724Ser	missense	Exon 10 of 11	ENSP00000532365.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000571 AC: 1 AN: 175222 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000231

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.14e-7 AC: 1 AN: 1094644 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361266

African (AFR) AF: 0.00 AC: 0 AN: 26330

American (AMR) AF: 0.00 AC: 0 AN: 35011

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19320

East Asian (EAS) AF: 0.00 AC: 0 AN: 30150

South Asian (SAS) AF: 0.00 AC: 0 AN: 53538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40161

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3036

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841184

Other (OTH) AF: 0.00 AC: 0 AN: 45914

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	M
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.73
Sift	Benign	0.46	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.79
MutPred		0.85		Gain of disorder (P = 0.1802)
MVP		0.98
MPC		1.5
ClinPred		0.59	D
GERP RS		5.3
Varity_R		0.44
gMVP		0.95
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs782041940; hg19: chrX-153008709;