rs4148030

Positions:

• chrX-153725208-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.-59C>T		5_prime_UTR_variant	1/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.-59C>T		5_prime_UTR_variant	1/11		XP_047297872.1
ABCD1	XM_047441917.1	c.-59C>T		5_prime_UTR_variant	1/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.-59C>T		5_prime_UTR_variant	1/10	1	NM_000033.4	ENSP00000218104	P1

Frequencies

GnomAD3 genomes AF: 0.0930 AC: 10472 AN: 112610 Hom.: 409 Cov.: 25 AF XY: 0.0877 AC XY: 3050 AN XY: 34784

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

Gnomad4 AFR exome AF: 0.0665

Gnomad4 AMR exome AF: 0.0550

Gnomad4 ASJ exome AF: 0.0667

Gnomad4 EAS exome AF: 0.0537

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.105

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

Gnomad4 AFR AF: 0.0676

Gnomad4 AMR AF: 0.0597

Gnomad4 ASJ AF: 0.0647

Gnomad4 EAS AF: 0.0508

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0887

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Adrenoleukodystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs4148030; hg19: chrX-152990663;