Genetic Variant ABCD1:p.Arg617Leu (chrX-153743056-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000033.4(ABCD1):c.1850G>T(p.Arg617Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R617P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

ABCD1
NM_000033.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.13

Publications

0 publications found

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 was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000033.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-153743056-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2438749.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4 link	c.1850G>T	p.Arg617Leu	missense_variant	Exon 8 of 10	ENST00000218104.6	NP_000024.2	P33897

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6 link	c.1850G>T	p.Arg617Leu	missense_variant	Exon 8 of 10	1	NM_000033.4	ENSP00000218104.3		P33897
PLXNB3-AS1	ENST00000434284.1 link	n.72-4478C>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1081625

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352435

African (AFR)

AF:

0.00

AC:

AN:

26143

American (AMR)

AF:

0.00

AC:

AN:

33329

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18965

East Asian (EAS)

AF:

0.00

AC:

AN:

29654

South Asian (SAS)

AF:

0.00

AC:

AN:

52065

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39241

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2879

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

833987

Other (OTH)

AF:

0.00

AC:

AN:

45362

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.70

BayesDel_noAF

Pathogenic

0.77

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.9

PhyloP100

8.1

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.89

Vest4

0.99

MutPred

1.0

Loss of MoRF binding (P = 0.0192);

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.99

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over