FEN1

protein-coding

flap structure-specific endonuclease 1

Gene summary

The protein encoded by this gene removes 5' overhanging flaps in DNA repair and processes the 5' ends of Okazaki fragments in lagging strand DNA synthesis. Direct physical interaction between this protein and AP endonuclease 1 during long-patch base excision repair provides coordinated loading of the proteins onto the substrate, thus passing the substrate from one enzyme to another. The protein is a member of the XPG/RAD2 endonuclease family and is one of ten proteins essential for cell-free DNA replication. DNA secondary structure can inhibit flap processing at certain trinucleotide repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by the protein encoded by this gene. Therefore, secondary structure can deter the protective function of this protein, leading to site-specific trinucleotide expansions. [provided by RefSeq, Jul 2008]

Previous symbols:

RAD2

MANE transcript

NM_004111.6

Inheritance

—

ClinVar variants

U:35B:1

Top phenotype

Non-immune hydrops fetalis

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr11:61,792,911-61,797,238

External References & Databases

Ensembl (ENSG00000168496)

Transcript & Mutation Effects

hg38 • Region Span ~4.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FEN1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 32

not providedTotal: 2

Non-immune hydrops fetalisTotal: 1

Hereditary breast ovarian cancer syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004111.6. 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 clinvar		1
missense			35 clinvar			35
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	35	1	0	36

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004111.6	RefSeq	NP_004102.1	1	MANE Select
ENST00000305885.3	Ensembl	ENSP00000305480.2	1	MANE Select
ENST00000535307.1	Ensembl	ENSP00000460402.1	2	Standard
ENST00000535723.1	Ensembl	ENSP00000445692.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fen1	Danio rerio	Structure: anatomical system Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

fen1

Danio rerio

Structure: anatomical system

Quality: quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Base excision repair - Homo sapiens (human)
DNA replication - Homo sapiens (human)
Non-homologous end-joining - Homo sapiens (human)
HDR through MMEJ (alt-NHEJ)
DNA Repair

Biological Process

double-strand break repair via homologous recombination
DNA replication
base-excision repair
double-strand break repair
UV protection

Molecular Function

magnesium ion binding
DNA binding
damaged DNA binding
double-stranded DNA binding
endonuclease activity

Cellular Component

nuclear chromosome, telomeric region
nucleus
nucleoplasm
nucleolus
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305885
Coding exons: 1
Length: 4608
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125747
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.36	169	227	0.745	0.0000139	2500
Missense (PolyPhen)		34	67.984	0.50012		670
Synonymous	1.78	67	88.3	0.759	0.00000491	766
Loss of Function	0.905	8	11.3	0.709	7.51e-7	124

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double- stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA. {ECO:0000255|HAMAP-Rule:MF_03140, ECO:0000269|PubMed:10744741, ECO:0000269|PubMed:11986308, ECO:0000269|PubMed:18443037, ECO:0000269|PubMed:20729856, ECO:0000269|PubMed:7961795, ECO:0000269|PubMed:8621570}.;

Recessive Scores

pRec: 0.543

Intolerance Scores

LoFtool: 0.701
RVIS EVS: -0.12
RVIS percentile EVS: 44.89

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.976

Gene Damage Prediction

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