rs201455322

Positions:

• chrX-153725973-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000033.4(ABCD1):​c.707G>A​(p.Arg236His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,209,571 control chromosomes in the GnomAD database, including 4 homozygotes. There are 251 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., 46 hem., cov: 26)
  • Exomes 𝑓: 0.00060 (2 hom. 205 hem.)
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 3.27

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018246949).
• BP6: Variant X-153725973-G-A is Benign according to our data. Variant chrX-153725973-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193034.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=5}. Variant chrX-153725973-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.707G>A	p.Arg236His	missense_variant	1/10	ENST00000218104.6	NP_000024.2
ABCD1	XM_047441916.1	c.707G>A	p.Arg236His	missense_variant	1/11		XP_047297872.1
ABCD1	XM_047441917.1	c.707G>A	p.Arg236His	missense_variant	1/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.707G>A	p.Arg236His	missense_variant	1/10	1	NM_000033.4	ENSP00000218104.3
ABCD1	ENST00000370129.4	c.152G>A	p.Arg51His	missense_variant	1/2	2		ENSP00000359147.3

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 131 AN: 113821 Hom.: 2 Cov.: 26 AF XY: 0.00128 AC XY: 46 AN XY: 35945

Gnomad AFR AF: 0.000127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00486

Gnomad ASJ AF: 0.0229

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000348

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000187

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.00142 AC: 254 AN: 178848 Hom.: 2 AF XY: 0.00125 AC XY: 82 AN XY: 65494

Gnomad AFR exome AF: 0.0000783

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.000147

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.000600 AC: 657 AN: 1095750 Hom.: 2 Cov.: 32 AF XY: 0.000566 AC XY: 205 AN XY: 362198

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.0000260

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00115 AC: 131 AN: 113821 Hom.: 2 Cov.: 26 AF XY: 0.00128 AC XY: 46 AN XY: 35945

Gnomad4 AFR AF: 0.000127

Gnomad4 AMR AF: 0.00486

Gnomad4 ASJ AF: 0.0229

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000348

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000187

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.00150 Hom.: 56

Bravo AF: 0.00133

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00119 AC: 8

ExAC AF: 0.00105 AC: 127

EpiCase AF: 0.000491

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adrenoleukodystrophy Uncertain:1 Benign:5

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	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	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2020	This variant is associated with the following publications: (PMID: 12175782, 23430809, 33151932) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ABCD1: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 16, 2014	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 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	0.21
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.073	T;T
Polyphen		1.0	D;.
Vest4		0.44
MVP		1.0
MPC		1.7
ClinPred		0.064	T
GERP RS		5.4
Varity_R		0.20
gMVP		0.56

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: rs201455322; hg19: chrX-152991428;