Variant NM_000033.4:c.1900G>A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000033.4(ABCD1):c.1900G>A(p.Ala634Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 10.0

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:

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

PLXNB3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4 link	c.1900G>A	p.Ala634Thr	missense_variant	Exon 9 of 10	ENST00000218104.6	NP_000024.2	P33897
ABCD1	XM_047441916.1 link	c.2200G>A	p.Ala734Thr	missense_variant	Exon 10 of 11		XP_047297872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6 link	c.1900G>A	p.Ala634Thr	missense_variant	Exon 9 of 10	1	NM_000033.4	ENSP00000218104.3		P33897
PLXNB3-AS1	ENST00000434284.1 link	n.72-4677C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.14e-7

AC:

AN:

1094646

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Pathogenic:1Uncertain:4

Mar 28, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This ABCD1 variant is absent from large population datasets and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classifies it as likely pathogenic and two as a variant of uncertain clinical significance. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this variant may create a potential cryptic splice site, however, its effect on splicing has not been studied experimentally to our knowledge. The clinical significance of c.1900G>A is uncertain at this time. -

Jun 20, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4_MOD, PM2_SUP, PP3 -

Oct 12, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 634 of the ABCD1 protein (p.Ala634Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with adrenoleukodystrophy (PMID: 35076462; external communication). ClinVar contains an entry for this variant (Variation ID: 282253). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCD1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Uncertain:3

May 17, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classified as a variant of uncertain significance in individuals with a positive newborn screen for X-ALD (PMID: 33920672, 35076462); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34946879, 33920672, 35076462, 34506099) -

Aug 18, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCD1-related disorder

Uncertain:1

Nov 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCD1 c.1900G>A variant is predicted to result in the amino acid substitution p.Ala634Thr. This variant was reported in individuals with borderline adrenoleukodystrophy, but was classified as a variant of uncertain significance (Burton et al. 2022. PubMed ID: 35076462; Supplemental table, Matteson et al. 2021. PubMed ID: 33920672; https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). Functional studies in fibroblasts suggest this variant impacts ABCD1 activity (van de Stadt et al. 2021. PubMed ID: 34946879). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. While we suspect that this variant could be pathogenic, at this time we interpret its clinical significance as uncertain due to insufficient functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.71

BayesDel_noAF

Pathogenic

0.77

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.3

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.95

MutPred

0.90

Gain of glycosylation at A634 (P = 0.0908);

MVP

1.0

MPC

1.5

ClinPred

1.0

GERP RS

5.3

Varity_R

0.79

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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