GEN1

Gene Facts

• HGNC Symbol: GEN1 (HGNC:26881)
• HGNC Name: GEN1 Holliday junction 5' flap endonuclease
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: FLJ40869, Gen
• %HI: 58.31
• pLI: 0
• LOEUF: 1.42
• Cytoband: 2p24.2
• Genomic Coordinates:

  GRCh37/hg19:	chr2:17935136-17970213
  GRCh38/hg38:	chr2:17753278-17788946

• MANE Select Transcript: NM_001130009.3 ENST00000381254.7
• 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 coo... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-25274
• ClinGen Curation ID: CCID:007203
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Dosage Sensitivity Unlikely (40)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/02/2021

Haploinsufficiency (HI) Score Details

• HI Score: 40
• HI Evidence Strength: Dosage Sensitivity Unlikely

HI Evidence

• PUBMED: 32487729
  Rausell et al. (2020) suggested that this gene is dosage sensitivity unlikely because it had at least one homozygous LoF variant present in >1% of the gnomAD population. An example of a homozygous likely LoF variant in this gene in gnomAD includes p.Lys839GlufsTer (1142 homozygous individuals).
• PUBMED: 22344438
  MacArthur et al. (2012) suggested that this gene is dosage sensitivity unlikely because it had at least one homozygous LoF variant present at >5% of the 1000 Genomes Project database.
• PUBMED: 28406212
  Saleheen et al. (2017) identified 1 adult individual in a Pakistani population with a homozygous LoF variant in this gene. The individuals were originally recruited for a study evaluating risk of myocardial infarction. Individuals within that study found to have homozygous predicted LOF variants were phenotyped for “more than 200 biochemical and disease traits”.
• PUBMED: 25807282
  Sulem et al. (2015) identified 1774 individuals in an Icelandic population with a homozygous LoF variant in this gene. This population was participating in a variety of disease projects and the researchers pulled this population to investigate how often homozygous LoF variants were found in this population.
• PUBMED: 32461654
  Karczewski et al. (2020) identifies 443,769 high confidence loss of function variants in the Genome Aggregation Database (gnomAD) population including this likely LoF variant (p.Lys839GlufsTer). Several methods were used to identify these genes including manual curation and utilizing LOEUF scores.

• HI Evidence Comments: This gene was classified as dosage sensitivity unlikely on 2/2/2021 based on review of population data as described in the PMIDs above. These genes all have at least one curated homozygous loss of function variant in 1% or greater of the gnomAD population dataset and some have also been observed in additional population datasets. As of January 2021, there are no disease associations found in OMIM, and no reports suggesting a Mendelian disease association in the literature. The gnomAD pLI score is 0 and the LOEUF score is .95 predicting that this gene is tolerant of LoF variation.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity