NM_000033.4:c.-59C>T

Variant names:

• chrX-153725208-C-T
• rs4148030
• NM_000033.4:c.-59C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000033.4(ABCD1):​c.-59C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,049,925 control chromosomes in the GnomAD database, including 4,866 homozygotes. There are 36,287 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (409 hom., 3059 hem., cov: 25)
  • Exomes 𝑓: 0.12 (4457 hom. 33228 hem.)
• Consequence: ABCD1 NM_000033.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0630
• Publications: 6 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-153725208-C-T is Benign according to our data. Variant chrX-153725208-C-T is described in ClinVar as Benign. ClinVar VariationId is 368042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.-59C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	NM_001440747.1	c.-59C>T		5_prime_UTR_variant	Exon 1 of 11		NP_001427676.1
ABCD1	XM_047441917.1	c.-59C>T		5_prime_UTR_variant	Exon 1 of 8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.-59C>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3

Frequencies

GnomAD3 genomes AF: 0.0930 AC: 10472 AN: 112610 Hom.: 409 Cov.: 25

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.0383

Gnomad AMR AF: 0.0598

Gnomad ASJ AF: 0.0647

Gnomad EAS AF: 0.0512

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0588

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0891

GnomAD4 exome AF: 0.115 AC: 107889 AN: 937262 Hom.: 4457 Cov.: 19 AF XY: 0.119 AC XY: 33228 AN XY: 279578

African (AFR) AF: 0.0665 AC: 1369 AN: 20573

American (AMR) AF: 0.0550 AC: 893 AN: 16246

Ashkenazi Jewish (ASJ) AF: 0.0667 AC: 935 AN: 14010

East Asian (EAS) AF: 0.0537 AC: 1353 AN: 25183

South Asian (SAS) AF: 0.155 AC: 6104 AN: 39436

European-Finnish (FIN) AF: 0.120 AC: 2878 AN: 23892

Middle Eastern (MID) AF: 0.0961 AC: 239 AN: 2488

European-Non Finnish (NFE) AF: 0.119 AC: 89913 AN: 755531

Other (OTH) AF: 0.105 AC: 4205 AN: 39903

GnomAD4 genome AF: 0.0930 AC: 10478 AN: 112663 Hom.: 409 Cov.: 25 AF XY: 0.0878 AC XY: 3059 AN XY: 34847

African (AFR) AF: 0.0676 AC: 2104 AN: 31134

American (AMR) AF: 0.0597 AC: 648 AN: 10854

Ashkenazi Jewish (ASJ) AF: 0.0647 AC: 171 AN: 2642

East Asian (EAS) AF: 0.0508 AC: 180 AN: 3544

South Asian (SAS) AF: 0.148 AC: 414 AN: 2791

European-Finnish (FIN) AF: 0.104 AC: 648 AN: 6208

Middle Eastern (MID) AF: 0.0461 AC: 10 AN: 217

European-Non Finnish (NFE) AF: 0.116 AC: 6140 AN: 53049

Other (OTH) AF: 0.0887 AC: 137 AN: 1545

Alfa AF: 0.101 Hom.: 713

Bravo AF: 0.0885

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 9.43% in ONEKG) based on the frequency threshold of 0.772% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. 1 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. A synonymous variant not located in a splice region. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Adrenoleukodystrophy Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		-0.063
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4148030; hg19: chrX-152990663;