X-153725065-C-G

Variant names:

• chrX-153725065-C-G
• rs781978041
• NM_000033.4:c.-202C>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000033.4(ABCD1):​c.-202C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 371,565 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 79 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., 23 hem., cov: 25)
  • Exomes 𝑓: 0.00062 (0 hom. 56 hem.)
• Consequence: ABCD1 NM_000033.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.129

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-153725065-C-G is Benign according to our data. Variant chrX-153725065-C-G is described in ClinVar as [Benign]. Clinvar id is 368041.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00066 (74/112088) while in subpopulation NFE AF= 0.000945 (50/52924). AF 95% confidence interval is 0.000736. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.-202C>G		5_prime_UTR_variant	Exon 1 of 10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.-202C>G		5_prime_UTR_variant	Exon 1 of 11		XP_047297872.1
ABCD1	XM_047441917.1	c.-202C>G		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	c.-202C>G		5_prime_UTR_variant	Exon 1 of 10	1	NM_000033.4	ENSP00000218104.3

Frequencies

GnomAD3 genomes AF: 0.000661 AC: 74 AN: 112033 Hom.: 0 Cov.: 25 AF XY: 0.000672 AC XY: 23 AN XY: 34229

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000372

Gnomad ASJ AF: 0.00531

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000945

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000620 AC: 161 AN: 259477 Hom.: 0 Cov.: 4 AF XY: 0.000697 AC XY: 56 AN XY: 80361

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000366

Gnomad4 ASJ exome AF: 0.00611

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000306

Gnomad4 NFE exome AF: 0.000575

Gnomad4 OTH exome AF: 0.000370

GnomAD4 genome AF: 0.000660 AC: 74 AN: 112088 Hom.: 0 Cov.: 25 AF XY: 0.000671 AC XY: 23 AN XY: 34294

Gnomad4 AFR AF: 0.000194

Gnomad4 AMR AF: 0.000372

Gnomad4 ASJ AF: 0.00531

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000945

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000854 Hom.: 5

Bravo AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adrenoleukodystrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs781978041; hg19: chrX-152990520;