rs1060500015
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate
The NM_024529.5(CDC73):c.188T>C(p.Leu63Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L63V) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
CDC73
NM_024529.5 missense
NM_024529.5 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 6.21
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CDC73
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
?
Variant 1-193125168-T-C is Pathogenic according to our data. Variant chr1-193125168-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 403886.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.188T>C | p.Leu63Pro | missense_variant | 2/17 | ENST00000367435.5 | |
CDC73 | XM_006711537.5 | c.188T>C | p.Leu63Pro | missense_variant | 2/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDC73 | ENST00000367435.5 | c.188T>C | p.Leu63Pro | missense_variant | 2/17 | 1 | NM_024529.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Parathyroid carcinoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of familial isolated hyperparathyroidism (PMID: 18755853, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 403886). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 63 of the CDC73 protein (p.Leu63Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;D;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
Polyphen
D;D;.
Vest4
0.94
MutPred
Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);
MVP
0.97
MPC
2.8
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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