rs398123101

Positions:

• chrX-153740082-GC-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000033.4(ABCD1):​c.1489-6del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,208,022 control chromosomes in the GnomAD database, including 103 homozygotes. There are 1,085 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (13 hom., 119 hem., cov: 24)
  • Exomes 𝑓: 0.0028 (90 hom. 966 hem.)
• Consequence: ABCD1 NM_000033.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.254

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]

LOC124905226 (HGNC:):

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant X-153740082-GC-G is Benign according to our data. Variant chrX-153740082-GC-G is described in ClinVar as [Likely_benign]. Clinvar id is 92315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153740082-GC-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1489-6del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000218104.6	NP_000024.2
LOC124905226	XR_007068350.1	n.1465del		non_coding_transcript_exon_variant	1/2
ABCD1	XM_047441916.1	c.1789-6del		splice_polypyrimidine_tract_variant, intron_variant			XP_047297872.1
ABCD1	XM_047441917.1	c.1545-6del		splice_polypyrimidine_tract_variant, intron_variant			XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1489-6del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000033.4	ENSP00000218104	P1
PLXNB3-AS1	ENST00000434284.1	n.72-1505del		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2	n.492-6del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 362 AN: 112875 Hom.: 13 Cov.: 24 AF XY: 0.00337 AC XY: 118 AN XY: 35023

Gnomad AFR AF: 0.000418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000836

Gnomad ASJ AF: 0.00226

Gnomad EAS AF: 0.0906

Gnomad SAS AF: 0.00253

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.00753 AC: 1360 AN: 180604 Hom.: 40 AF XY: 0.00678 AC XY: 444 AN XY: 65478

Gnomad AFR exome AF: 0.000762

Gnomad AMR exome AF: 0.000331

Gnomad ASJ exome AF: 0.00138

Gnomad EAS exome AF: 0.0924

Gnomad SAS exome AF: 0.00113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00284 AC: 3115 AN: 1095093 Hom.: 90 Cov.: 31 AF XY: 0.00268 AC XY: 966 AN XY: 360949

Gnomad4 AFR exome AF: 0.000417

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00114

Gnomad4 EAS exome AF: 0.0861

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.00836

GnomAD4 genome AF: 0.00320 AC: 361 AN: 112929 Hom.: 13 Cov.: 24 AF XY: 0.00339 AC XY: 119 AN XY: 35087

Gnomad4 AFR AF: 0.000417

Gnomad4 AMR AF: 0.000835

Gnomad4 ASJ AF: 0.00226

Gnomad4 EAS AF: 0.0909

Gnomad4 SAS AF: 0.00217

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000563

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00165 Hom.: 5

Bravo AF: 0.00428

Asia WGS AF: 0.0430 AC: 109 AN: 2521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 21, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 24, 2019	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2020	This variant is associated with the following publications: (PMID: 14556192, 24788897, 16996397, 22995991, 23835273) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs398123101; hg19: chrX-153005536;