GEN1
protein-codingGEN1 Holliday junction 5' flap endonuclease
Gene summary
This gene encodes a member of the Rad2/xeroderma pigmentosum group G nuclease family, whose members are characterized by N-terminal and internal xeroderma pigmentosum group G nuclease domains followed by helix-hairpin-helix domains and disordered C-terminal domains. The protein encoded by this gene is involved in resolution of Holliday junctions, which are intermediate four-way structures that covalently link DNA during homologous recombination and double-strand break repair. The protein resolves Holliday junctions by creating dual incisions across the junction to produce nicked duplex products that can be ligated. In addition, this protein has been found to localize to centrosomes where it has been implicated in regulation of centrosome integrity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~35.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0016248
Submitter: ClinGen
Inheritance Pattern: AD
Disease ID:MONDO:0016419
Submitter: ClinGen
*GEN1* encodes an endonuclease that is involved in resolution of Holliday junctions during homologous recombination and double-strand break repair. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is no disease associated with *GEN1* in OMIM, and curations to refute or dispute can be split when needed. **Summary of Case-Control Data: 0 point** This gene-disease relationship has been studied in at least 2 case-control studies at the aggregate or single variant level. In 2021, a large case-control study [BCAC (PMID: 33471991); with more than 48 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in *GEN1* and breast cancer. In addition, another case-control study (PMID: 20512659) with smaller populations did not show an association of *GEN1* variants with breast cancer. **Summary of Experimental Data: 1.25 point** While case control studies did not support the gene-disease association, there is experimental evidence suggesting the function as a Holliday junction-resolving endonuclease (PMID: 19020614). Wyatt et al. showed that cells depleted of *GEN1* exhibited defects in chromosome segregation and anaphase bridge formation after DNA damage (PMID: 24076221). *GEN1* depletion also showed aberrant centrosome numbers and formation of multiple spindle poles during mitosis (PMID: 23166748). In addition, Sun et al. demonstrated that GEN1 expression is correlated with mammary epithelial cell proliferation and differentiation in various physiological stages (PMID: 24980922). **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between *GEN1* and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 12/13/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GEN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001130009.3. 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 | 3 | 349 | 3 | 355 | ||
| missense | 1017 | 48 | 4 | 1069 | ||
| nonsense | 16 | 16 | ||||
| start loss | 0 | |||||
| frameshift | 36 | 36 | ||||
| splice donor/acceptor (+/-2bp) | 12 | 12 | ||||
| Total | 0 | 0 | 1084 | 397 | 7 | 1488 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001123481.3 | 13 | MANE Select | |
| Ensembl | ENSP00000370653.2 | 13 | MANE Select | |
| RefSeq | NP_872431.5 | 13 | Standard | |
| Ensembl | ENSP00000318977.7 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
- DNA Repair
- DNA Double-Strand Break Repair
- Homology Directed Repair
- Resolution of D-loop Structures through Holliday Junction Intermediates
Biological Process
- double-strand break repair via homologous recombination
- regulation of centrosome duplication
- replication fork processing
- resolution of recombination intermediates
- resolution of mitotic recombination intermediates
Molecular Function
- magnesium ion binding
- four-way junction DNA binding
- endodeoxyribonuclease activity
- crossover junction endodeoxyribonuclease activity
- 5'-flap endonuclease activity
Cellular Component
- nucleoplasm
- centrosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000381254
- Coding exons
- 13
- Length
- 31508
- Individuals with no LoFs
- 104901
- Homozygous LoFs
- 1034
- Heterozygous LoFs
- 19813
- Defined
- 125748
- p
- 0.0866
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0999 | 451 | 457 | 0.987 | 0.0000217 | 5996 |
| Missense (PolyPhen) | 110 | 120.21 | 0.91507 | 1548 | ||
| Synonymous | 0.261 | 157 | 161 | 0.974 | 0.00000763 | 1640 |
| Loss of Function | 1.81 | 29 | 41.6 | 0.698 | 0.00000208 | 558 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.019 | 0.019 | notable |
| Latino/Admixed American | 0.043 | 0.043 | notable |
| Ashkenazi Jewish | 0.099 | 0.099 | notable |
| East Asian | 0.13 | 0.13 | notable |
| Finnish | 0.094 | 0.094 | notable |
| European (Non-Finnish) | 0.11 | 0.11 | notable |
| South Asian | 0.048 | 0.047 | notable |
| Other | 0.091 | 0.091 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Endonuclease which resolves Holliday junctions (HJs) by the introduction of symmetrically related cuts across the junction point, to produce nicked duplex products in which the nicks can be readily ligated. Four-way DNA intermediates, also known as Holliday junctions, are formed during homologous recombination and DNA repair, and their resolution is necessary for proper chromosome segregation (PubMed:19020614, PubMed:26682650). Cleaves HJs by a nick and counter-nick mechanism involving dual coordinated incisions that lead to the formation of ligatable nicked duplex products. Cleavage of the first strand is rate limiting, while second strand cleavage is rapid. Largely monomeric, dimerizes on the HJ and the first nick occurs upon dimerization at the junction (PubMed:26578604). Efficiently cleaves both single and double HJs contained within large recombination intermediates. Exhibits a weak sequence preference for incision between two G residues that reside in a T-rich region of DNA (PubMed:28049850). Has also endonuclease activity on 5'- flap and replication fork (RF) DNA substrates (PubMed:26578604). {ECO:0000269|PubMed:19020614, ECO:0000269|PubMed:26578604, ECO:0000269|PubMed:26682650, ECO:0000269|PubMed:28049850}.;
Recessive Scores
- pRec
- 0.0983
Intolerance Scores
- LoFtool
- 0.994
- RVIS EVS
- 2.2
- RVIS percentile EVS
- 98.13
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.110
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |