rs183021839

Positions:

• chrX-153725304-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000033.4(ABCD1):​c.38A>C​(p.Asn13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,146,578 control chromosomes in the GnomAD database, including 6 homozygotes. There are 979 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., 90 hem., cov: 25)
  • Exomes 𝑓: 0.0027 (6 hom. 889 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0820

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00509429).
• BP6: Variant X-153725304-A-C is Benign according to our data. Variant chrX-153725304-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 368044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153725304-A-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 90 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.38A>C	p.Asn13Thr	missense_variant	1/10	ENST00000218104.6
ABCD1	XM_047441916.1	c.38A>C	p.Asn13Thr	missense_variant	1/11
ABCD1	XM_047441917.1	c.38A>C	p.Asn13Thr	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.38A>C	p.Asn13Thr	missense_variant	1/10	1	NM_000033.4	P1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 251 AN: 112804 Hom.: 0 Cov.: 25 AF XY: 0.00257 AC XY: 90 AN XY: 35004

Gnomad AFR AF: 0.000192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000368

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00203 AC: 174 AN: 85534 Hom.: 1 AF XY: 0.00169 AC XY: 41 AN XY: 24244

Gnomad AFR exome AF: 0.000215

Gnomad AMR exome AF: 0.000932

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00341

GnomAD4 exome AF: 0.00268 AC: 2772 AN: 1033723 Hom.: 6 Cov.: 32 AF XY: 0.00267 AC XY: 889 AN XY: 332361

Gnomad4 AFR exome AF: 0.000372

Gnomad4 AMR exome AF: 0.000683

Gnomad4 ASJ exome AF: 0.000111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00222 AC: 251 AN: 112855 Hom.: 0 Cov.: 25 AF XY: 0.00257 AC XY: 90 AN XY: 35065

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000367

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00406 Hom.: 48

Bravo AF: 0.00117

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000531 AC: 3

ExAC AF: 0.000619 AC: 38

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2021	- -

Adrenoleukodystrophy Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	Variant summary: ABCD1 c.38A>C (p.Asn13Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 1146578 control chromosomes in the gnomAD database (v4), including 979 hemizygotes and 6 homozygotes, strongly suggesting the variant is a benign polymorphism. To our knowledge, no occurrences of c.38A>C with strong evidence for causality have been reported in individuals affected with Adrenoleukodystrophy. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Dvorakova_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11438993). ClinVar contains an entry for this variant (Variation ID: 368044). Based on the evidence outlined above, the variant was classified as benign. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2016

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	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.26
DANN	Benign	0.29
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.55
MPC		0.57
ClinPred		0.0017	T
GERP RS		3.3
Varity_R		0.055
gMVP		0.21

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: rs183021839; hg19: chrX-152990759;