rs797046101
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001029896.2(WDR45):c.397C>T(p.Arg133Ter) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
WDR45
NM_001029896.2 stop_gained
NM_001029896.2 stop_gained
Scores
2
1
2
Clinical Significance
Conservation
PhyloP100: 2.25
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-49076469-G-A is Pathogenic according to our data. Variant chrX-49076469-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49076469-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WDR45 | NM_001029896.2 | c.397C>T | p.Arg133Ter | stop_gained | 6/11 | ENST00000376372.9 | |
WDR45 | NM_007075.4 | c.400C>T | p.Arg134Ter | stop_gained | 7/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WDR45 | ENST00000376372.9 | c.397C>T | p.Arg133Ter | stop_gained | 6/11 | 1 | NM_001029896.2 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurodegeneration with brain iron accumulation 5 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 02, 2021 | PVS1, PS2, PS4, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Mar 06, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 07, 2015 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Universidade de São Paulo | Mar 16, 2022 | This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity. This variant was disclosed in a girl presenting with intellectual disability and X-chromosome inactivation skewing. - |
Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Feb 09, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 26, 2023 | This premature translational stop signal has been observed in individual(s) with neurodegeneration with brain iron accumulation (NBIA), epileptic spasms and developmental delay, and West syndrome (PMID: 23176820, 25744623, 26609730, 27030146). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 212592). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg134*) in the WDR45 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WDR45 are known to be pathogenic (PMID: 23176820, 24368176, 24621584, 25744623, 26790960, 27030146, 27652284, 28554332). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23176820, 29981852, 25744623, 23687123, 26609730, 30369941, 25326635, 29445477, 27030146, 33084218, 33843443, 34077496) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
X-linked cerebral-cerebellar-coloboma syndrome syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant was previously reported as pathogenic and was found once in our laboratory de novo in a 3-year-old female with infantile spasms, global developmental delay, and normal brain MRI. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A;A;A;A;N
Vest4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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