GeneBe

CDC73

protein-coding

cell division cycle 73, the group of MicroRNA protein coding host genes|Paf1/RNA polymerase II complex

Gene summary

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]

Previous symbols:
  • C1orf28
  • HRPT2
  • HRPT1

MANE transcript

NM_024529.5

Inheritance

AD

ClinVar variants

P:161U:750B:455

Top phenotype

Hyperparathyroidism 1; Hyperparathyroidism 2 with jaw tumors; Carcinoma, parathyroid

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr1:193,121,983-193,254,815

External References & Databases

Ensembl (ENSG00000134371)NCBI Gene (79577)OMIM (607393)HGNC:16783GenCCUniProt (Q6P1J9)AlphaFoldClinVar (CDC73)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~132.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperparathyroidism 2 with jaw tumorsDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007768

Submitter: ClinGen

There is abundant published evidence associating the CDC73 gene with hyperparathyroidism-jaw tumor syndrome, since the gene-disease relationship was first proposed by Carpten et al. (2002). Multiple case level studies have been performed with HPT-JT patients that have variants in the CDC73 gene. Loss of nuclear expression and immunoreactivity of Parafibromin was reported in Parathyroid Carcinoma of HPT-JT patients. Functional characterization of three mutations from CDC73 patients caused cell overgrowth in cell proliferation assay. CDC73 deficient mice (Both Cdc73+/− mice and the conditional Cdc73+/L/PTH- Cre and Cdc73L/L/PTH-Cre mice) develop parathyroid and uterine tumours. All of these types of evidence are consistent with a definitive relationship between the CDC73 gene and hyperparathyroidism-jaw tumor syndrome.

hyperparathyroidism 2 with jaw tumorsDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007768

Submitter: Ambry Genetics

hyperparathyroidism 2 with jaw tumorsDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007768

Submitter: G2P

familial isolated hyperparathyroidismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015027

Submitter: Orphanet

parathyroid gland carcinomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012004

Submitter: Ambry Genetics

hyperparathyroidism 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007767

Submitter: Labcorp Genetics (formerly Invitae)

parathyroid gland carcinomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012004

Submitter: Labcorp Genetics (formerly Invitae)

hyperparathyroidism 2 with jaw tumorsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007768

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hyperparathyroidism 1; Hyperparathyroidism 2 with jaw tumors; Carcinoma, parathyroidAD

Manifestation: Endocrine; Oncologic; Renal

Intervention: Endocrine; Oncologic

Rationale: Parathyroidectomy (or medical treatment in individuals unable to undergo parathyroidectomy) may be necessary to normalize calcium levels, and parathyroid adenomas may recur; Surveillance and early diagnosis/treatment of specific manifestations, including jaw tumor recurrence, parathyroid carcinoma, and renal neoplasms, is indicated

Refs: 11157996; 3592449; 12434154; 14585940; 14715834; 14985403; 15531515; 15606373; 16720667; 17639062; 17666472; 21361849; 20301744; 22187299; 23652676; 23757631Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDC73 variants in ClinVar

17 Conditions Cataloged
Parathyroid carcinomaTotal: 1376
Hereditary cancer-predisposing syndromeTotal: 1013
Hyperparathyroidism 1Total: 138
Hyperparathyroidism 2 with jaw tumorsTotal: 115
not providedTotal: 110
not specifiedTotal: 100
CDC73-related disorderTotal: 27
Familial hyperparathyroidism or Hypocalciuric hypercalcaemiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024529.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
7
clinvar
434
clinvar
1
clinvar
 442
missense
1
clinvar
3
clinvar
724
clinvar
20
clinvar
 748
nonsense
39
clinvar
7
clinvar
1
clinvar
 47
start loss
6
clinvar
 6
frameshift
72
clinvar
11
clinvar
4
clinvar
 87
splice donor/acceptor (+/-2bp)
6
clinvar
16
clinvar
14
clinvar
 36
Total1243775045411366

Highest pathogenic variant AF is 0.0000020524328

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_024529.5RefSeqNP_078805.317MANE Select
ENST00000367435.5EnsemblENSP00000356405.417MANE Select
ENST00000635846.1EnsemblENSP00000490035.114Standard
ENST00000635846.2EnsemblENSP00000490035.114Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
cdc73Danio rerio

Structure: cardiac muscle cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • WNT-Ncore
  • Endoderm Differentiation
  • Signaling by WNT
  • Signal Transduction
  • Gene expression (Transcription)

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • endodermal cell fate commitment
  • transcription by RNA polymerase II
  • transcription elongation from RNA polymerase II promoter
  • mRNA polyadenylation

Molecular Function

  • RNA polymerase II complex binding
  • protein binding

Cellular Component

  • nuclear chromosome, telomeric region
  • nucleus
  • nucleoplasm
  • cytosol
  • Cdc73/Paf1 complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000367435
Coding exons
17
Length
131885
Individuals with no LoFs
125715
Homozygous LoFs
0
Heterozygous LoFs
6
Defined
125721
p
0.0000239
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.731193010.3950.00001633456
Missense (PolyPhen)2590.9280.274941089
Synonymous-0.37010398.31.050.000004971025
Loss of Function5.52341.20.07280.00000262407

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000360.000035rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways. May be involved in cell cycle progression through the regulation of cyclin D1/PRAD1 expression. Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non- phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both indepentently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Connects PAF1C with the cleavage and polyadenylation specificity factor (CPSF) complex and the cleavage stimulation factor (CSTF) complex, and with Wnt signaling. Involved in polyadenylation of mRNA precursors. {ECO:0000269|PubMed:15580289, ECO:0000269|PubMed:15632063, ECO:0000269|PubMed:15923622, ECO:0000269|PubMed:16630820, ECO:0000269|PubMed:16989776, ECO:0000269|PubMed:19136632, ECO:0000269|PubMed:19952111, ECO:0000269|PubMed:20178742, ECO:0000269|PubMed:20541477, ECO:0000269|PubMed:21329879}.;
Disease
DISEASE: Hyperparathyroidism 1 (HRPT1) [MIM:145000]: An autosomal dominant disorder characterized by hypercalcemia, elevated parathyroid hormone (PTH) levels, and uniglandular or multiglandular parathyroid hyperplasia, adenomas, and carcinomas. {ECO:0000269|PubMed:12434154, ECO:0000269|PubMed:12960210, ECO:0000269|PubMed:15632063, ECO:0000269|PubMed:16487440, ECO:0000269|PubMed:18755853}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperparathyroidism 2 with jaw tumors (HRPT2) [MIM:145001]: An autosomal dominant neoplasia syndrome characterized by primary hyperparathyroidism, ossifying fibroma of the maxilla and/or mandible, renal tumor, and uterine tumors. It is associated with increased risk of parathyroid cancer. {ECO:0000269|PubMed:12434154, ECO:0000269|PubMed:15613436, ECO:0000269|PubMed:16487440}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parathyroid carcinoma (PRTC) [MIM:608266]: These cancers characteristically result in more profound clinical manifestations of hyperparathyroidism than do parathyroid adenomas, the most frequent cause of primary hyperparathyroidism. Early en bloc resection of the primary tumor is the only curative treatment. {ECO:0000269|PubMed:14585940}. Note=The gene represented in this entry is involved in disease pathogenesis.;

Recessive Scores

pRec
0.156

Intolerance Scores

LoFtool
0.112
RVIS EVS
-0.38
RVIS percentile EVS
27.42

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.994

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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