rs727502864
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_032856.5(WDR73):c.766_767insC(p.Arg256ProfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,610,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
WDR73
NM_032856.5 frameshift
NM_032856.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.32
Genes affected
WDR73 (HGNC:25928): (WD repeat domain 73) The protein encoded by this gene is thought to contain multiple WD40 repeats. WD40 repeats are motifs that contain 40-60 amino acids, and usually end with Trp-Asp (WD). This protein is found in the cytoplasm during interphase, but accumulates at the spindle poles and astral microtubules during mitosis. Reduced expression of this gene results in abnormalities in the size and morphology of the nucleus. Mutations in this gene have been associated with Galloway-Mowat syndrome PMID: 25466283), which is a rare autosomal recessive disorder that affects both the central nervous system and kidneys. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 15-84645587-C-CG is Pathogenic according to our data. Variant chr15-84645587-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WDR73 | NM_032856.5 | c.766_767insC | p.Arg256ProfsTer18 | frameshift_variant | 7/8 | ENST00000434634.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WDR73 | ENST00000434634.7 | c.766_767insC | p.Arg256ProfsTer18 | frameshift_variant | 7/8 | 1 | NM_032856.5 | P1 | |
ENST00000348993.9 | n.7089dup | non_coding_transcript_exon_variant | 4/4 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000960 AC: 14AN: 1458726Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10AN XY: 725414
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Galloway-Mowat syndrome 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The homozygous p.Arg256ProfsTer18 variant in WDR73 was identified by our study in one individual with Galloway-Mowat syndrome. This variant was seen in 0.006677% (1/14976) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727502864). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The homozygous p.Arg256ProfsTer18 variant in WDR73 has been reported in one Turkish individual with Galloway-Mowat syndrome. This individual's unaffected parents and siblings were heterozygous for the variant or did not have the variant (PMID: 25466283). This nonsense variant leads to a premature termination codon at position 274, which is predicted to lead to a truncated or absent protein. A knock-out zebrafish model for the WDR73 gene has a phenotype that matches Galloway-Mowat syndrome and at least two loss of function variants across multiple exons have been reported in association with Galloway-Mowat syndrome in ClinVar (PMID: 25466283). Loss of function of the WDR73 gene is a moderately established disease mechanism in autosomal recessive Galloway-Mowat syndrome. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 162611). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 04, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 30, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at