rs864321693
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_016628.5(WAC):c.112del(p.Ser38AlafsTer154) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
WAC
NM_016628.5 frameshift
NM_016628.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.32
Genes affected
WAC (HGNC:17327): (WW domain containing adaptor with coiled-coil) The protein encoded by this gene contains a WW domain, which is a protein module found in a wide range of signaling proteins. This domain mediates protein-protein interactions and binds proteins containing short linear peptide motifs that are proline-rich or contain at least one proline. This gene product shares 94% sequence identity with the WAC protein in mouse, however, its exact function is not known. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 10-28535594-TA-T is Pathogenic according to our data. Variant chr10-28535594-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 219144.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-28535594-TA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WAC | NM_016628.5 | c.112del | p.Ser38AlafsTer154 | frameshift_variant | 3/14 | ENST00000354911.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WAC | ENST00000354911.9 | c.112del | p.Ser38AlafsTer154 | frameshift_variant | 3/14 | 1 | NM_016628.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2015 | The c.112delA variant in the WAC gene has not been reported previously as pathogenicnor as a benign polymorphism, to our knowledge. The c.112delA deletion causes a frameshiftstarting with codon Serine 38, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 154 of the new reading frame, denoted p.Ser38AlafsX154. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.112delA deletion 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. Therefore, we interpret c.112delA as a pathogenic variant. - |
DeSanto-Shinawi syndrome due to WAC point mutation Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2015 | - - |
Computational scores
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Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
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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