X-49074865-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001029896.2(WDR45):c.1021G>A(p.Gly341Arg) variant causes a missense change. 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 (★).
Frequency
Genomes: not found (cov: 24)
Consequence
WDR45
NM_001029896.2 missense
NM_001029896.2 missense
Scores
12
3
2
Clinical Significance
Conservation
PhyloP100: 7.15
Genes affected
WDR45 (HGNC:28912): (WD repeat domain 45) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene has a pseudogene at chromosome 4q31.3. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity and full-length nature of some variants have not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.877
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WDR45 | NM_001029896.2 | c.1021G>A | p.Gly341Arg | missense_variant | 11/11 | ENST00000376372.9 | NP_001025067.1 | |
WDR45 | NM_007075.4 | c.1024G>A | p.Gly342Arg | missense_variant | 12/12 | NP_009006.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WDR45 | ENST00000376372.9 | c.1021G>A | p.Gly341Arg | missense_variant | 11/11 | 1 | NM_001029896.2 | ENSP00000365551.3 | ||
ENSG00000288053 | ENST00000376358.4 | c.521+499G>A | intron_variant | 2 | ENSP00000365536.3 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD3 genomes
Cov.:
24
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 24
GnomAD4 genome
Cov.:
24
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neurodegeneration with brain iron accumulation 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 15, 2022 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WDR45 protein function. ClinVar contains an entry for this variant (Variation ID: 1054825). This variant has not been reported in the literature in individuals affected with WDR45-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 342 of the WDR45 protein (p.Gly342Arg). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;.;T;.;.;.;.;T
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;D;D;D;D;.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;.;D;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;.;D;D;D;D;.
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;.;.;.;D;D;D;D;.
Vest4
MutPred
Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);.;.;.;.;.;.;.;.;
MVP
MPC
1.8
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
DS_AG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.