ANAPC1
protein-codinganaphase promoting complex subunit 1, the group of Anaphase promoting complex |MicroRNA protein coding host genes
Gene summary
This gene encodes a subunit of the anaphase-promoting complex. This complex is an E3 ubiquitin ligase that regulates progression through the metaphase to anaphase portion of the cell cycle by ubiquitinating proteins which targets them for degradation. [provided by RefSeq, Dec 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~273.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0016368
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0016368
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016368
Submitter: ClinGen
The *ANAPC1* gene, located on chromosome 2 at 2q13, encodes anaphase promoting complex subunit 1, which is a component of the anaphase promoting complex/cyclosome (APC/C). ANAPC1 was first reported in relation to autosomal recessive Rothmund-Thomson syndrome type 1 in 2019 (Ajeawung et al., PMID: 31303264). Rothmund-Thomson syndrome type 1 is a subform of Rothmund-Thomson syndrome (RTS) presenting with a characteristic facial rash (poikiloderma) and is frequently associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, and rapidly progressive bilateral juvenile cataracts. Patients may also have growth retardation and genital, skeletal, and dental abnormalities but do not appear to have an increased risk of developing cancer. At least 11 patients from eight families have been described (PMID: 31303264, 35664819). Five variants (1 recurrent intronic, 2 frameshift, 1 canonical splice, and 1 large deletion) reported in eight unrelated probands in two publications (PMID: 31303264, 35664819) are included in this curation. Please note that 0.5 pts were awarded for the recurrent intronic variant observed in trans with the large deletion, which could not be entered, resulting in a total of 8.5 genetic evidence points. Co-segregation of *ANAPC1* variants was observed in three affected family members from three families, including from the Plain community; however, none of the families met the criteria to score segregation. Notably, a deep intronic variant, c.2705-198C>T, which has been shown to result in the inclusion of a pseudoexon and introduction of a premature truncation codon, has been identified in every patient described to date. The mechanism of pathogenicity may involve loss of function, as suggested by reduced *ANAPC1* mRNA and protein expression in patient fibroblasts, but additional investigation is needed. This gene-disease relationship is also supported by experimental evidence, including a biochemical function in cell cycle regulation, DNA repair and replication, and chromosomal and genomic stability that is shared with at least one gene associated with a similar phenotype; evidence of a cell cycling defect in patient fibroblasts; and an increased rate of cataract development in heterozygous knockout mice (PMID: 31303264). In summary, there is moderate evidence supporting the relationship between *ANAPC1* and autosomal recessive Rothmund-Thomson syndrome type 1. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on September 20, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0016368
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0016368
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0016368
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0016368
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dental; Endocrine; Dermatologic; Genitourinary; Musculoskeletal; Ophthalmologic
Intervention: Endocrine
Rationale: Awareness of endocrine manifestations, including growth hormone deficiency, may allow early recognition and treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ANAPC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022662.4. 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 | 4 | 26 | 3 | 33 | ||
| missense | 220 | 11 | 231 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 4 | 5 | |||
| Total | 2 | 0 | 230 | 37 | 3 | 272 |
Highest pathogenic variant AF is 0.000026289154
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_073153.1 | 47 | MANE Select | |
| Ensembl | ENSP00000339109.3 | 47 | MANE Select | |
| Ensembl | ENSP00000396695.1 | 37 | Standard | |
| Ensembl | ENSP00000405375.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- Oocyte meiosis - Homo sapiens (human)
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- HTLV-I infection - Homo sapiens (human)
- Progesterone-mediated oocyte maturation - Homo sapiens (human)
Biological Process
- metaphase/anaphase transition of mitotic cell cycle
- anaphase-promoting complex-dependent catabolic process
- cell division
- protein K11-linked ubiquitination
- regulation of mitotic cell cycle phase transition
Molecular Function
- ubiquitin protein ligase activity
Cellular Component
- nucleoplasm
- anaphase-promoting complex
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000341068
- Coding exons
- 47
- Length
- 118420
- Individuals with no LoFs
- 125608
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 53
- Defined
- 125661
- p
- 0.000211
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.987 | 681 | 757 | 0.899 | 0.0000379 | 12564 |
| Missense (PolyPhen) | 167 | 231.91 | 0.72011 | 4315 | ||
| Synonymous | -0.343 | 277 | 270 | 1.03 | 0.0000140 | 3690 |
| Loss of Function | 6.61 | 16 | 79.7 | 0.201 | 0.00000395 | 1327 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.00076 | 0.00075 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00017 | 0.00015 | rare |
| South Asian | 0.00013 | 0.000098 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. {ECO:0000269|PubMed:18485873}.;
Recessive Scores
- pRec
- 0.0958
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.600
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |