chrX-153743743-G-C

Variant names:

• chrX-153743743-G-C
• rs2229539
• NM_000033.4:c.*8G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 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 -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 VariationId is 92313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.*8G>C		3_prime_UTR	Exon 10 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.*8G>C		3_prime_UTR	Exon 11 of 11	NP_001427676.1
	PLXNB3-AS1	NR_199693.1		n.90-5165C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.*8G>C		3_prime_UTR	Exon 10 of 10	ENSP00000218104.3
	PLXNB3-AS1	ENST00000434284.1	TSL:3	n.72-5165C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.708 AC: 77353 AN: 109318 Hom.: 19973 Cov.: 21

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

GnomAD2 exomes AF: 0.673 AC: 70334 AN: 104522 AF XY: 0.674

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 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

African (AFR) AF: 0.853 AC: 21390 AN: 25072

American (AMR) AF: 0.702 AC: 20251 AN: 28851

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 11147 AN: 18600

East Asian (EAS) AF: 0.649 AC: 17845 AN: 27517

South Asian (SAS) AF: 0.765 AC: 38182 AN: 49911

European-Finnish (FIN) AF: 0.662 AC: 19849 AN: 29969

Middle Eastern (MID) AF: 0.651 AC: 1859 AN: 2854

European-Non Finnish (NFE) AF: 0.648 AC: 532385 AN: 821659

Other (OTH) AF: 0.672 AC: 29798 AN: 44327

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

African (AFR) AF: 0.844 AC: 25364 AN: 30060

American (AMR) AF: 0.705 AC: 7376 AN: 10463

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 1543 AN: 2618

East Asian (EAS) AF: 0.614 AC: 2079 AN: 3384

South Asian (SAS) AF: 0.766 AC: 1967 AN: 2568

European-Finnish (FIN) AF: 0.638 AC: 3613 AN: 5660

Middle Eastern (MID) AF: 0.660 AC: 142 AN: 215

European-Non Finnish (NFE) AF: 0.650 AC: 33943 AN: 52238

Other (OTH) AF: 0.683 AC: 1027 AN: 1503

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

Mar 07, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 25, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Adrenoleukodystrophy Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 17, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

History of neurodevelopmental disorder Benign:1

Aug 27, 2015

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: 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	-0.91
CADD	Benign	2.3
DANN	Benign	0.53
PhyloP100		-0.38
Mutation Taster		=100/0	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: rs2229539; hg19: chrX-153009197; COSMIC: COSV99497697; COSMIC: COSV99497697;