rs1060500020
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_024529.5(CDC73):c.4del(p.Ala2?) variant causes a frameshift, start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
CDC73
NM_024529.5 frameshift, start_lost
NM_024529.5 frameshift, start_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.31
Genes affected
CDC73 (HGNC:16783): (cell division cycle 73) This gene encodes a tumor suppressor that is involved in transcriptional and post-transcriptional control pathways. The protein is a component of the the PAF protein complex, which associates with the RNA polymerase II subunit POLR2A and with a histone methyltransferase complex. This protein appears to facilitate the association of 3' mRNA processing factors with actively-transcribed chromatin. Mutations in this gene have been linked to hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, and parathyroid carcinoma. [provided by RefSeq, Jul 2009]
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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 62 pathogenic variants in the truncated region.
PS1
?
Another start lost variant in NM_024529.5 (CDC73) was described as [Pathogenic] in ClinVar as 3267
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-193122202-TG-T is Pathogenic according to our data. Variant chr1-193122202-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 403893.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDC73 | NM_024529.5 | c.4del | p.Ala2? | frameshift_variant, start_lost | 1/17 | ENST00000367435.5 | |
CDC73 | XM_006711537.5 | c.4del | p.Ala2? | frameshift_variant, start_lost | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDC73 | ENST00000367435.5 | c.4del | p.Ala2? | frameshift_variant, start_lost | 1/17 | 1 | NM_024529.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Parathyroid carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 16, 2016 | For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in CDC73 are known to be pathogenic (PMID: 12434154). This sequence change deletes 1 nucleotide from exon 1 of the CDC73 mRNA (c.4delG), causing a frameshift at codon 2. This creates a premature translational stop signal (p.Ala2Argfs*19) and is expected to result in an absent or disrupted protein product. - |
Computational scores
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Calibrated prediction
Score
Prediction
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