X-153736112-A-G

Position:

chrX-153736112-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_000033.4(ABCD1):c.1082A>G(p.Asp361Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000922 in 1,084,253 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D361Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000092 ( 0 hom. 2 hem. )

Consequence

ABCD1
NM_000033.4 missense, splice_region

Scores

Splicing: ADA: 0.002822

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.28

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:

LOC124905226 (HGNC:):

LOC124905226 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_benign. Variant got -2 ACMG points.

PM1

In a domain ABC transmembrane type-1 (size 292) in uniprot entity ABCD1_HUMAN there are 177 pathogenic changes around while only 40 benign (82%) in NM_000033.4

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCD1	NM_000033.4 linkuse as main transcript	c.1082A>G	p.Asp361Gly	missense_variant, splice_region_variant	3/10	ENST00000218104.6
LOC124905226	XR_007068350.1 linkuse as main transcript	n.4239T>C		non_coding_transcript_exon_variant	2/2
ABCD1	XM_047441916.1 linkuse as main transcript	c.1082A>G	p.Asp361Gly	missense_variant, splice_region_variant	3/11
ABCD1	XM_047441917.1 linkuse as main transcript	c.1082A>G	p.Asp361Gly	missense_variant, splice_region_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ABCD1	ENST00000218104.6 linkuse as main transcript	c.1082A>G	p.Asp361Gly	missense_variant, splice_region_variant	3/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1 linkuse as main transcript	n.581-153T>C		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2 linkuse as main transcript	n.85A>G		splice_region_variant, non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000220

AC:

AN:

181632

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000497

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000922

AC:

AN:

1084253

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

354227

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 361 of the ABCD1 protein (p.Asp361Gly). This variant is present in population databases (no rsID available, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with ABCD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1451028). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.54

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.46

Sift

Benign

0.32

Sift4G

Benign

0.44

Polyphen

0.0010

Vest4

0.55

MutPred

0.37

Gain of glycosylation at S360 (P = 0.0285);

MVP

0.99

MPC

0.87

ClinPred

0.096

GERP RS

4.5

Varity_R

0.20

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0028

dbscSNV1_RF

Benign

0.032

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