15-53609531-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_182758.4(WDR72):c.2934G>A(p.Trp978*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,252 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
Consequence
NM_182758.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WDR72 | ENST00000360509.10 | c.2934G>A | p.Trp978* | stop_gained | Exon 17 of 20 | 1 | NM_182758.4 | ENSP00000353699.5 | ||
WDR72 | ENST00000396328.5 | c.2934G>A | p.Trp978* | stop_gained | Exon 17 of 20 | 1 | ENSP00000379619.1 | |||
WDR72 | ENST00000559418.5 | c.2964G>A | p.Trp988* | stop_gained | Exon 16 of 19 | 5 | ENSP00000452765.1 | |||
WDR72 | ENST00000557913.5 | c.2925G>A | p.Trp975* | stop_gained | Exon 17 of 20 | 5 | ENSP00000453378.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251006Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135646
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461252Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726914
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Amelogenesis imperfecta hypomaturation type 2A3 Pathogenic:3
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Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported to be associated with WDR72 related disorder (ClinVar ID: VCV000000232, PMID:19853237). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Each parent is heterozygous for the variant (PM3_P, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:1
The W978X variant in the WDR72 gene has been reported previously in the homozygous state in an individual with hypomaturation amelogenesis imperfecta (El-Sayed et al., 2009). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W978X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret W978X as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at