GEN1

GEN1 Holliday junction 5' flap endonuclease

Basic information

Region (hg38): 2:17753858-17788946

Links

ENSG00000178295 ∙ NCBI:348654 ∙ OMIM:612449 ∙ HGNC:26881 ∙ Uniprot:Q17RS7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial ovarian cancer (No Known Disease Relationship), mode of inheritance: AD
• hereditary breast carcinoma (Refuted Evidence), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GEN1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GEN1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	126	4	133
missense			361	12	10	383
nonsense			13			13
start loss						0
frameshift			28		1	29
inframe indel			8			8
splice donor/acceptor (+/-2bp)			9			9
splice region			10	11	2	23
non coding			2	35	44	81
Total	0	0	424	173	59

Variants in GEN1

This is a list of pathogenic ClinVar variants found in the GEN1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-17754138-G-T		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
2-17755795-A-T		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
2-17755897-T-G		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
2-17757644-A-T		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
2-17758468-T-C		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
2-17759914-T-G		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
2-17759951-T-C			Uncertain significance (Dec 05, 2021)
2-17759955-T-A			Uncertain significance (Mar 27, 2022)
2-17759959-T-G		not specified	Uncertain significance (Nov 22, 2024)
2-17759961-G-A			Likely benign (Feb 02, 2021)
2-17759965-C-A		not specified	Uncertain significance (Jan 17, 2024)
2-17759968-A-G			Uncertain significance (Dec 08, 2022)
2-17759985-G-A		not specified	Likely benign (Nov 26, 2024)
2-17759991-C-A			Uncertain significance (Nov 10, 2021)
2-17759992-A-G			Uncertain significance (Feb 02, 2023)
2-17759997-C-G			Likely benign (Jan 01, 2023)
2-17760001-C-T		not specified	Uncertain significance (Dec 08, 2024)
2-17760002-G-A			Uncertain significance (Jan 07, 2023)
2-17760002-G-T		not specified	Uncertain significance (Nov 27, 2024)
2-17760027-A-T		not specified	Likely benign (Nov 30, 2024)
2-17760028-G-A		not specified	Uncertain significance (Dec 08, 2024)
2-17760028-G-C			Uncertain significance (Apr 23, 2020)
2-17760040-C-G		not specified	Uncertain significance (Dec 08, 2024)
2-17760048-G-T		not specified	Likely benign (Nov 20, 2024)
2-17760054-G-A			Likely benign (Apr 22, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GEN1	protein_coding	protein_coding	ENST00000381254	13	31508

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.73e-15	0.693	104901	1034	19813	125748	0.0866

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0999	451	457	0.987	0.0000217	5996
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0622	0.0623
Ashkenazi Jewish	0.0993	0.0989
East Asian	0.126	0.128
Finnish	0.0939	0.0944
European (Non-Finnish)	0.113	0.112
Middle Eastern	0.126	0.128
South Asian	0.0476	0.0473
Other	0.0908	0.0909

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: 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;Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR) (Consensus)

Recessive Scores

• pRec: 0.0983

Intolerance Scores

• loftool: 0.994
• rvis_EVS: 2.2
• rvis_percentile_EVS: 98.13

Haploinsufficiency Scores

• pHI: 0.0998
• hipred: N
• hipred_score: 0.123
• ghis: 0.471

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.110

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Gen1

Gene ontology

• 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;positive regulation of mitotic cell cycle spindle assembly checkpoint
• Cellular component: nucleoplasm;centrosome
• Molecular function: magnesium ion binding;four-way junction DNA binding;endodeoxyribonuclease activity;crossover junction endodeoxyribonuclease activity;5'-flap endonuclease activity;5'-3' exodeoxyribonuclease activity;protein homodimerization activity;flap endonuclease activity