ORC1
protein-codingorigin recognition complex subunit 1, the group of Origin recognition complex |AAA ATPases
Gene summary
The origin recognition complex (ORC) is a highly conserved six subunits protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. The protein encoded by this gene is the largest subunit of the ORC complex. While other ORC subunits are stable throughout the cell cycle, the levels of this protein vary during the cell cycle, which has been shown to be controlled by ubiquitin-mediated proteolysis after initiation of DNA replication. This protein is found to be selectively phosphorylated during mitosis. It is also reported to interact with MYST histone acetyltransferase 2 (MyST2/HBO1), a protein involved in control of transcription silencing. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]
- ORC1L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0016817
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009143
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009143
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009143
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009143
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ORC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004153.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 6 | 97 | 3 | 107 | |
| missense | 4 | 5 | 180 | 24 | 5 | 218 |
| nonsense | 6 | 1 | 7 | |||
| start loss | 0 | |||||
| frameshift | 8 | 4 | 3 | 15 | ||
| splice donor/acceptor (+/-2bp) | 2 | 6 | 6 | 14 | ||
| Total | 20 | 17 | 195 | 121 | 8 | 361 |
Highest pathogenic variant AF is 0.00029739115
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004144.2 | 16 | MANE Select | |
| Ensembl | ENSP00000360623.3 | 16 | MANE Select | |
| RefSeq | NP_001177747.1 | 16 | Standard | |
| RefSeq | NP_001177748.1 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| orc1 | Danio rerio | Structure: otolith Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- Cell Cycle
- Mitotic G1-G1-S phases
- Retinoblastoma (RB) in Cancer
- G1 to S cell cycle control
Biological Process
- G1/S transition of mitotic cell cycle
- regulation of transcription involved in G1/S transition of mitotic cell cycle
- mitotic cell cycle
- DNA replication
- DNA replication initiation
Molecular Function
- DNA binding
- chromatin binding
- DNA replication origin binding
- protein binding
- ATP binding
Cellular Component
- nuclear chromosome, telomeric region
- origin recognition complex
- nucleus
- nucleoplasm
- nuclear origin of replication recognition complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371568
- Coding exons
- 16
- Length
- 31631
- Individuals with no LoFs
- 125696
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 52
- Defined
- 125748
- p
- 0.000207
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.235 | 455 | 469 | 0.969 | 0.0000291 | 5568 |
| Missense (PolyPhen) | 125 | 134.25 | 0.93108 | 1564 | ||
| Synonymous | 0.574 | 174 | 184 | 0.946 | 0.0000113 | 1754 |
| Loss of Function | 2.20 | 29 | 44.9 | 0.646 | 0.00000302 | 503 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00019 | 0.00019 | rare |
| South Asian | 0.00036 | 0.00036 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.;
- Disease
- DISEASE: Meier-Gorlin syndrome 1 (MGORS1) [MIM:224690]: A syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal. {ECO:0000269|PubMed:21358631, ECO:0000269|PubMed:21358632, ECO:0000269|PubMed:21358633}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.120
Intolerance Scores
- RVIS EVS
- 0.61
- RVIS percentile EVS
- 82.93
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |