rs770804941
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_182758.4(WDR72):c.88C>T(p.Arg30Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,884 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
WDR72
NM_182758.4 stop_gained
NM_182758.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.85
Genes affected
WDR72 (HGNC:26790): (WD repeat domain 72) This gene encodes a protein with eight WD-40 repeats. Mutations in this gene have been associated with amelogenesis imperfecta hypomaturation type 2A3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]
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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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-53733062-G-A is Pathogenic according to our data. Variant chr15-53733062-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WDR72 | NM_182758.4 | c.88C>T | p.Arg30Ter | stop_gained | 2/20 | ENST00000360509.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WDR72 | ENST00000360509.10 | c.88C>T | p.Arg30Ter | stop_gained | 2/20 | 1 | NM_182758.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152086Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251028Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135650
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GnomAD4 exome AF: 0.0000527 AC: 77AN: 1461798Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727206
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74304
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Amelogenesis imperfecta hypomaturation type 2A3 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 21, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 30, 2021 | The WDR72 c.88C>T variant is classified as a LIKELY PATHOGENIC variant (PVS1, PM2) The variant is a single nucleotide change from a cytosine to a thymine at position 88 which is predicted to change the Arginine at position 30 in the protein to a premature STOP codon, which is predicted to lead to a truncated or absent protein (PVS1). The variant is in dbSNP (rs770804941) but its low frequency in population databases (gnomAD 7/282418, 0 homozygotes) is consistent with a recessive carrier frequency (PM2). The variant has been reported in the ClinVar as likely pathogenic (Variation ID: 517616), and in the HGMD as VUS (Accession#: CM190501). - |
Amelogenesis imperfecta Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2018 | The p.Arg30X variant (NM_182758.2 c.88C>T) in WDR72 has not been previously repo rted in the literature, but has been identified in 2/34392 of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs770804941). Although this variant has been seen in the general population , its frequency is low enough to be consistent with a recessive carrier frequenc y. This nonsense variant leads to a premature termination codon at position 30, which is predicted to lead to a truncated or absent protein. Biallelic loss of f unction of the WDR72 gene has been associated with amelogenesis imperfecta. In s ummary, although additional studies are required to fully establish its clinical significance, the p.Arg30X variant is likely pathogenic based on a predicted nu ll effect. ACMG/AMP Criteria applied: PVS1; PM2 (Richards 2015). - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
Splicing
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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