rs2229539

Positions:

• chrX-153743743-G-C
• chrX-153743743-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000033.4(ABCD1):​c.*8G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (19982 hom., 22195 hem., cov: 21)
  • Exomes 𝑓: 0.66 (154206 hom. 227087 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.382

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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-153743743-G-C is Benign according to our data. Variant chrX-153743743-G-C is described in ClinVar as [Benign]. Clinvar id is 92313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153743743-G-C is described in Lovd as [Benign]. Variant chrX-153743743-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.*8G>C		3_prime_UTR_variant	10/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.*8G>C		3_prime_UTR_variant	11/11		XP_047297872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.*8G>C		3_prime_UTR_variant	10/10	1	NM_000033.4	ENSP00000218104.3
PLXNB3-AS1	ENST00000434284.1	n.72-5165C>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.708 AC: 77353 AN: 109318 Hom.: 19973 Cov.: 21 AF XY: 0.699 AC XY: 22133 AN XY: 31644

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.673 AC: 70334 AN: 104522 Hom.: 15937 AF XY: 0.674 AC XY: 23445 AN XY: 34766

Gnomad AFR exome AF: 0.847

Gnomad AMR exome AF: 0.696

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.577

Gnomad SAS exome AF: 0.764

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.641

Gnomad OTH exome AF: 0.664

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.660 AC: 692706 AN: 1048760 Hom.: 154206 Cov.: 35 AF XY: 0.664 AC XY: 227087 AN XY: 341782

Gnomad4 AFR exome AF: 0.853

Gnomad4 AMR exome AF: 0.702

Gnomad4 ASJ exome AF: 0.599

Gnomad4 EAS exome AF: 0.649

Gnomad4 SAS exome AF: 0.765

Gnomad4 FIN exome AF: 0.662

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.672

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.708 AC: 77420 AN: 109369 Hom.: 19982 Cov.: 21 AF XY: 0.700 AC XY: 22195 AN XY: 31705

Gnomad4 AFR AF: 0.844

Gnomad4 AMR AF: 0.705

Gnomad4 ASJ AF: 0.589

Gnomad4 EAS AF: 0.614

Gnomad4 SAS AF: 0.766

Gnomad4 FIN AF: 0.638

Gnomad4 NFE AF: 0.650

Gnomad4 OTH AF: 0.683

Alfa AF: 0.669 Hom.: 7845

Bravo AF: 0.719

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Adrenoleukodystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 17, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2015

This alteration is classified as benign based on a combination of the following: 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.53

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: rs2229539; hg19: chrX-153009197;