rs150151955

chrX-153726023-C-GchrX-153726023-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000033.4(ABCD1):c.757C>G(p.Leu253Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,204,688 control chromosomes in the GnomAD database, including 1 homozygotes. There are 461 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L253F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., 18 hem., cov: 26)
  • Exomes 𝑓: 0.0013 (1 hom. 443 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.23

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000033.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.044420302).
• BP6: Variant X-153726023-C-G is Benign according to our data. Variant chrX-153726023-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 377034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153726023-C-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.757C>G	p.Leu253Val	missense_variant	1/10	ENST00000218104.6
ABCD1	XM_047441916.1	c.757C>G	p.Leu253Val	missense_variant	1/11
ABCD1	XM_047441917.1	c.757C>G	p.Leu253Val	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.757C>G	p.Leu253Val	missense_variant	1/10	1	NM_000033.4	P1
ABCD1	ENST00000370129.4	c.202C>G	p.Leu68Val	missense_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000614 AC: 70 AN: 113921 Hom.: 0 Cov.: 26 AF XY: 0.000499 AC XY: 18 AN XY: 36041

Gnomad AFR AF: 0.000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000347

Gnomad FIN AF: 0.000622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000829 AC: 143 AN: 172513 Hom.: 0 AF XY: 0.000598 AC XY: 36 AN XY: 60237

Gnomad AFR exome AF: 0.000241

Gnomad AMR exome AF: 0.0000750

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00126 AC: 1369 AN: 1090714 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 443 AN XY: 357750

Gnomad4 AFR exome AF: 0.000267

Gnomad4 AMR exome AF: 0.0000287

Gnomad4 ASJ exome AF: 0.0000526

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000561

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.000614 AC: 70 AN: 113974 Hom.: 0 Cov.: 26 AF XY: 0.000499 AC XY: 18 AN XY: 36104

Gnomad4 AFR AF: 0.000254

Gnomad4 AMR AF: 0.000183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000348

Gnomad4 FIN AF: 0.000622

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00118 Hom.: 22

Bravo AF: 0.000680

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.00149 AC: 10

ExAC AF: 0.00112 AC: 136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 27, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ABCD1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2018	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30487145, 33151932) -

Adrenoleukodystrophy Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 08, 2019

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Uncertain	0.77	D;D
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.53	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.97	N;N
REVEL	Uncertain	0.61
Sift	Benign	0.19	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.37	B;.
Vest4		0.33
MVP		1.0
MPC		0.63
ClinPred		0.014	T
GERP RS		5.4
Varity_R		0.26
gMVP		0.83

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: rs150151955; hg19: chrX-152991478;