rs782161942

Positions:

chrX-153725307-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000033.4(ABCD1):c.41C>G(p.Thr14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000619 in 1,148,054 control chromosomes in the GnomAD database, including 1 homozygotes. There are 200 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00044 ( 1 hom., 7 hem., cov: 25)

Exomes 𝑓: 0.00064 ( 0 hom. 193 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 0.462

Variant links:

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]

ABCD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019428253).

BP6

Variant X-153725307-C-G is Benign according to our data. Variant chrX-153725307-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458643.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=4, Benign=1}. Variant chrX-153725307-C-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCD1	NM_000033.4 linkuse as main transcript	c.41C>G	p.Thr14Arg	missense_variant	1/10	ENST00000218104.6
ABCD1	XM_047441916.1 linkuse as main transcript	c.41C>G	p.Thr14Arg	missense_variant	1/11
ABCD1	XM_047441917.1 linkuse as main transcript	c.41C>G	p.Thr14Arg	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6 linkuse as main transcript	c.41C>G	p.Thr14Arg	missense_variant	1/10	1	NM_000033.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000442

AC:

AN:

113096

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

AN XY:

35242

show subpopulations

Gnomad AFR

AF:

0.0000961

Gnomad AMI

AF:

0.0103

Gnomad AMR

AF:

0.000642

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000620

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000394

AC:

AN:

86391

Hom.:

AF XY:

0.000282

AC XY:

AN XY:

24845

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000149

Gnomad NFE exome

AF:

0.000974

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000639

AC:

661

AN:

1034958

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

193

AN XY:

333206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000412

Gnomad4 AMR exome

AF:

0.000151

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000316

Gnomad4 NFE exome

AF:

0.000768

Gnomad4 OTH exome

AF:

0.000504

GnomAD4 genome

AF:

0.000442

AC:

AN:

113096

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

AN XY:

35242

show subpopulations

Gnomad4 AFR

AF:

0.0000961

Gnomad4 AMR

AF:

0.000642

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000620

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000437

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00138

AC:

ExAC

AF:

0.0000653

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Uncertain:2Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Uncertain:1Benign:3

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	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ABCD1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2021	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2020

This alteration is classified as likely 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. -

ABCD1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 06, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.43

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.55

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.57

REVEL

Benign

0.21

Sift

Benign

0.17

Sift4G

Benign

0.49

Polyphen

0.24

Vest4

0.073

MutPred

0.40

Gain of solvent accessibility (P = 0.0055);

MVP

0.87

MPC

0.65

ClinPred

0.025

GERP RS

2.2

Varity_R

0.14

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over