chrX-49075573-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001029896.2(WDR45):c.697C>T(p.Arg233Ter) 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 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: 1.29
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-49075573-G-A is Pathogenic according to our data. Variant chrX-49075573-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49075573-G-A is described in Lovd as [Pathogenic]. Variant chrX-49075573-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WDR45 | NM_001029896.2 | c.697C>T | p.Arg233Ter | stop_gained | 8/11 | ENST00000376372.9 | |
WDR45 | NM_007075.4 | c.700C>T | p.Arg234Ter | stop_gained | 9/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WDR45 | ENST00000376372.9 | c.697C>T | p.Arg233Ter | stop_gained | 8/11 | 1 | NM_001029896.2 | P4 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
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 | Mar 17, 2022 | PVS1 PS2 PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 17, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2023 | This premature translational stop signal has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 23176820, 23687123, 28932395, 29171013, 29981852). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 41912). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg234*) 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). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 07, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodegeneration with brain iron accumulation 5 (MIM#300894). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic (ClinVar), and observed in a heterozygous individual with developmental delay, in whom the variant was de novo (PMID: 29981852). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | research | TIDEX, University of British Columbia | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2022 | 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: 27159028, 23687123, 23176820, 26795593, 28932395, 29171013, 26725113, 29286531, 30842224, 31618753, 33504798, 30542205, 34490615, 32342562, 29981852, 31785789) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 27, 2014 | The c.700C>T (p.R234*) alteration, located in exon 9 (coding exon 7) of the WDR45 gene, consists of a C to T substitution at nucleotide position 700. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 234. Premature stop codons are typically deleterious in nature (Richards, 2015). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the WDR45 c.700C>T (p.R234*) alteration was not observed among 6,453 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The amino acid change has been observed in affected individuals: _x000D_ The c.700C>T (p.R234*) alteration has been reported in a 39 year-old female patient with beta-propeller protein-associated neurodegeneration (BPAN), an X-linked dominant form of neurodegeneration with brain iron accumulation (Haack, 2012; Hayflick, 2013). This patient's phenotype included developmental delay and intellectual disability, progressive psychomotor slowing in adolescence, dystonia and Parkinsonism with a positive response to L-DOPA, limited expressive language, stroke, and epilepsy characterized by absence, atonic, and febrile seizures. Brain MRI in this patient revealed iron accumulation in the substantia nigra and globus pallidus and T1 hyperintense "halo" in the midbrain. Based on the available evidence, this alteration is classified as pathogenic. - |
Seizure;C0344482:Hypoplasia of the corpus callosum;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C1837658:Delayed gross motor development;C1854882:Absent speech Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;A;A;A;A;A;D
Vest4
ClinPred
D
GERP RS
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