rs41302176

chrX-153729216-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000033.4(ABCD1):c.901-16C>T 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 0.0112 in 1,210,356 control chromosomes in the GnomAD database, including 87 homozygotes. There are 4,322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (5 hom., 252 hem., cov: 23)
  • Exomes 𝑓: 0.012 (82 hom. 4070 hem.)
• Consequence: ABCD1 NM_000033.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0110

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-153729216-C-T is Benign according to our data. Variant chrX-153729216-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153729216-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0081 (913/112729) while in subpopulation NFE AF= 0.0131 (698/53238). AF 95% confidence interval is 0.0123. There are 5 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.901-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000218104.6
ABCD1	XM_047441916.1	c.901-16C>T		splice_polypyrimidine_tract_variant, intron_variant
ABCD1	XM_047441917.1	c.901-16C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.901-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000033.4	P1
ABCD1	ENST00000370129.4	c.346-16C>T		splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 912 AN: 112675 Hom.: 5 Cov.: 23 AF XY: 0.00724 AC XY: 252 AN XY: 34801

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.0501

Gnomad AMR AF: 0.00317

Gnomad ASJ AF: 0.00714

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000361

Gnomad FIN AF: 0.00995

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.00790

GnomAD3 exomes AF: 0.00765 AC: 1395 AN: 182246 Hom.: 7 AF XY: 0.00734 AC XY: 492 AN XY: 67034

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00589

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000577

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.0115 AC: 12676 AN: 1097627 Hom.: 82 Cov.: 31 AF XY: 0.0112 AC XY: 4070 AN XY: 363051

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00738

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000702

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.00900

GnomAD4 genome AF: 0.00810 AC: 913 AN: 112729 Hom.: 5 Cov.: 23 AF XY: 0.00723 AC XY: 252 AN XY: 34865

Gnomad4 AFR AF: 0.00170

Gnomad4 AMR AF: 0.00317

Gnomad4 ASJ AF: 0.00714

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000362

Gnomad4 FIN AF: 0.00995

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.00780

Alfa AF: 0.0102 Hom.: 81

Bravo AF: 0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Adrenoleukodystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 29, 2021	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.8
Dann	Benign	0.74

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: rs41302176; hg19: chrX-152994671;