X-153743257-C-T

Variant names:

• chrX-153743257-C-T
• rs141110958
• NM_000033.4:c.1902C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000033.4(ABCD1):​c.1902C>T​(p.Ala634Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,207,028 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00015 (0 hom. 67 hem.)
• Consequence: ABCD1 NM_000033.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -4.84
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-153743257-C-T is Benign according to our data. Variant chrX-153743257-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 528351.
• BP7: Synonymous conserved (PhyloP=-4.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000213 (24/112677) while in subpopulation EAS AF = 0.00508 (18/3544). AF 95% confidence interval is 0.00328. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 24 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.1902C>T	p.Ala634Ala	synonymous	Exon 9 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.2202C>T	p.Ala734Ala	synonymous	Exon 10 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-4679G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.1902C>T	p.Ala634Ala	synonymous	Exon 9 of 10	ENSP00000218104.3
	PLXNB3-AS1	ENST00000434284.1	TSL:3	n.72-4679G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000213 AC: 24 AN: 112625 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000929

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00506

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000406 AC: 71 AN: 174817 AF XY: 0.000262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00393

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000776

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000154 AC: 169 AN: 1094351 Hom.: 0 Cov.: 32 AF XY: 0.000186 AC XY: 67 AN XY: 361001

African (AFR) AF: 0.00 AC: 0 AN: 26326

American (AMR) AF: 0.0000286 AC: 1 AN: 34981

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19317

East Asian (EAS) AF: 0.00246 AC: 74 AN: 30128

South Asian (SAS) AF: 0.000767 AC: 41 AN: 53460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3026

European-Non Finnish (NFE) AF: 0.0000440 AC: 37 AN: 841059

Other (OTH) AF: 0.000349 AC: 16 AN: 45904

GnomAD4 genome AF: 0.000213 AC: 24 AN: 112677 Hom.: 0 Cov.: 23 AF XY: 0.000172 AC XY: 6 AN XY: 34841

African (AFR) AF: 0.00 AC: 0 AN: 31095

American (AMR) AF: 0.0000927 AC: 1 AN: 10782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00508 AC: 18 AN: 3544

South Asian (SAS) AF: 0.00 AC: 0 AN: 2747

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6237

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

European-Non Finnish (NFE) AF: 0.0000940 AC: 5 AN: 53176

Other (OTH) AF: 0.00 AC: 0 AN: 1539

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000283

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adrenoleukodystrophy Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Uncertain:1

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Aug 08, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.34
DANN	Benign	0.91
PhyloP100		-4.8
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs141110958; hg19: chrX-153008711;