X-153726146-G-A
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000033.4(ABCD1):c.880G>A(p.Ala294Thr) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A294V) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 26)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
ABCD1
NM_000033.4 missense
NM_000033.4 missense
Scores
11
5
Clinical Significance
Conservation
PhyloP100: 9.59
Publications
2 publications found
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]
BCAP31 (HGNC:16695): (B cell receptor associated protein 31) This gene encodes a member of the B-cell receptor associated protein 31 superfamily. The encoded protein is a multi-pass transmembrane protein of the endoplasmic reticulum that is involved in the anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi and in caspase 8-mediated apoptosis. Microdeletions in this gene are associated with contiguous ABCD1/DXS1375E deletion syndrome (CADDS), a neonatal disorder. Alternative splicing of this gene results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 16. [provided by RefSeq, Jan 2012]
BCAP31 Gene-Disease associations (from GenCC):
- severe motor and intellectual disabilities-sensorineural deafness-dystonia syndromeInheritance: AR, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
PM1
In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000033.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant X-153726146-G-A is Pathogenic according to our data. Variant chrX-153726146-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430421.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ABCD1 | TSL:1 MANE Select | c.880G>A | p.Ala294Thr | missense | Exon 1 of 10 | ENSP00000218104.3 | P33897 | ||
| ABCD1 | c.880G>A | p.Ala294Thr | missense | Exon 1 of 11 | ENSP00000532366.1 | ||||
| ABCD1 | c.880G>A | p.Ala294Thr | missense | Exon 1 of 11 | ENSP00000532365.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
26
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1046048Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 331318
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1046048
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
331318
African (AFR)
AF:
AC:
0
AN:
25230
American (AMR)
AF:
AC:
0
AN:
28346
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
17122
East Asian (EAS)
AF:
AC:
0
AN:
28270
South Asian (SAS)
AF:
AC:
0
AN:
46851
European-Finnish (FIN)
AF:
AC:
0
AN:
36749
Middle Eastern (MID)
AF:
AC:
0
AN:
3969
European-Non Finnish (NFE)
AF:
AC:
0
AN:
815535
Other (OTH)
AF:
AC:
0
AN:
43976
GnomAD4 genome
GnomAD4 genome
Cov.:
26
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
4
-
-
Adrenoleukodystrophy (4)
1
1
-
not provided (2)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of glycosylation at A294 (P = 0.0591)
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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