chrX-153725306-A-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000033.4(ABCD1):​c.40A>G​(p.Thr14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,147,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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. T14R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 25)
Exomes 𝑓: 0.000052 ( 0 hom. 21 hem. )

Consequence

ABCD1
NM_000033.4 missense

Scores

1
2
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.522

Publications

1 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 Gene-Disease associations (from GenCC):
  • adrenoleukodystrophy
    Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
  • X-linked cerebral adrenoleukodystrophy
    Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
  • hereditary spastic paraplegia
    Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
  • Hirschsprung disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • adrenomyeloneuropathy
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.088257074).
BP6
Variant X-153725306-A-G is Benign according to our data. Variant chrX-153725306-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434063.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 54 XL,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCD1NM_000033.4 linkc.40A>G p.Thr14Ala missense_variant Exon 1 of 10 ENST00000218104.6 NP_000024.2 P33897
ABCD1NM_001440747.1 linkc.40A>G p.Thr14Ala missense_variant Exon 1 of 11 NP_001427676.1
ABCD1XM_047441917.1 linkc.40A>G p.Thr14Ala missense_variant Exon 1 of 8 XP_047297873.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCD1ENST00000218104.6 linkc.40A>G p.Thr14Ala missense_variant Exon 1 of 10 1 NM_000033.4 ENSP00000218104.3 P33897

Frequencies

GnomAD3 genomes
AF:
0.0000266
AC:
3
AN:
112902
Hom.:
0
Cov.:
25
show subpopulations
Gnomad AFR
AF:
0.0000321
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00131
GnomAD2 exomes
AF:
0.0000812
AC:
7
AN:
86193
AF XY:
0.0000405
show subpopulations
Gnomad AFR exome
AF:
0.000212
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000158
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000522
AC:
54
AN:
1034197
Hom.:
0
Cov.:
32
AF XY:
0.0000631
AC XY:
21
AN XY:
332611
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
24197
American (AMR)
AF:
0.00
AC:
0
AN:
26379
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18023
East Asian (EAS)
AF:
0.0000750
AC:
2
AN:
26662
South Asian (SAS)
AF:
0.000124
AC:
6
AN:
48380
European-Finnish (FIN)
AF:
0.0000316
AC:
1
AN:
31623
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3012
European-Non Finnish (NFE)
AF:
0.0000443
AC:
36
AN:
812327
Other (OTH)
AF:
0.000206
AC:
9
AN:
43594
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000266
AC:
3
AN:
112902
Hom.:
0
Cov.:
25
AF XY:
0.0000285
AC XY:
1
AN XY:
35080
show subpopulations
African (AFR)
AF:
0.0000321
AC:
1
AN:
31155
American (AMR)
AF:
0.00
AC:
0
AN:
10890
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2650
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3550
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2821
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6275
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
240
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
53113
Other (OTH)
AF:
0.00131
AC:
2
AN:
1530
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000812
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ABCD1: BS2 -

Adrenoleukodystrophy Benign:2
Oct 07, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Apr 14, 2017
Genetic Services Laboratory, University of Chicago
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
Benign
0.061
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
13
DANN
Benign
0.81
DEOGEN2
Benign
0.36
T
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.56
T
M_CAP
Pathogenic
0.30
D
MetaRNN
Benign
0.088
T
MetaSVM
Benign
-0.35
T
MutationAssessor
Benign
0.55
N
PhyloP100
0.52
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.34
N
REVEL
Benign
0.19
Sift
Benign
0.23
T
Sift4G
Benign
0.62
T
Polyphen
0.0
B
Vest4
0.014
MutPred
0.25
Loss of phosphorylation at T14 (P = 0.0168);
MVP
0.88
MPC
0.55
ClinPred
0.032
T
GERP RS
3.9
PromoterAI
0.021
Neutral
Varity_R
0.081
gMVP
0.46
Mutation Taster
=94/6
polymorphism

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

Other links and lift over

dbSNP: rs781900720; hg19: chrX-152990761; API