FAN1

FANCD2 and FANCI associated nuclease 1

Basic information

Region (hg38): 15:30890559-30943108

Previous symbols: [ "KIAA1018", "MTMR15" ]

Links

ENSG00000198690 ∙ NCBI:22909 ∙ OMIM:613534 ∙ HGNC:29170 ∙ Uniprot:Q9Y2M0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Lynch syndrome (Supportive), mode of inheritance: AD
• karyomegalic interstitial nephritis (Supportive), mode of inheritance: AR
• karyomegalic interstitial nephritis (Strong), mode of inheritance: AR
• hereditary nonpolyposis colon cancer (Limited), mode of inheritance: AD
• karyomegalic interstitial nephritis (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Interstitial nephritis, karyomegalic	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Gastrointestinal; Renal	7847351; 8546134; 16678356; 17304531; 22772369
Individuals may suffer renal failure, and renal transplant has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FAN1 gene.

• not_provided (206 variants)
• Karyomegalic_interstitial_nephritis (203 variants)
• Inborn_genetic_diseases (135 variants)
• FAN1-related_disorder (56 variants)
• not_specified (4 variants)
• Hereditary_breast_ovarian_cancer_syndrome (2 variants)
• Kidney_failure (1 variants)
• Hereditary_cancer (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FAN1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000014967.5. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	73	5	82
missense	1	2	250	25	2	280
nonsense	8	18				26
start loss			1			1
frameshift	12	21	3			36
splice donor/acceptor (+/-2bp)	1	4				5
Total	22	45	258	98	7

Highest pathogenic variant AF is 0.00011897

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FAN1	protein_coding	protein_coding	ENST00000362065	13	39257

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.65e-25	0.00448	125429	0	319	125748	0.00127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0474	571	568	1.01	0.0000316	6675
Missense in Polyphen		173	184.99	0.93519		2190
Synonymous	-0.889	235	218	1.08	0.0000125	1959
Loss of Function	0.881	42	48.6	0.864	0.00000276	568

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00213	0.00212
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00219	0.00218
Finnish	0.000786	0.000786
European (Non-Finnish)	0.00130	0.00129
Middle Eastern	0.00219	0.00218
South Asian	0.00166	0.00163
Other	0.00114	0.00114

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Nuclease required for the repair of DNA interstrand cross-links (ICL) recruited at sites of DNA damage by monoubiquitinated FANCD2. Specifically involved in repair of ICL- induced DNA breaks by being required for efficient homologous recombination, probably in the resolution of homologous recombination intermediates (PubMed:20603015, PubMed:20603016, PubMed:20603073, PubMed:20671156, PubMed:24981866, PubMed:25430771). Not involved in DNA double-strand breaks resection (PubMed:20603015, PubMed:20603016). Acts as a 5'-3' exonuclease that anchors at a cut end of DNA and cleaves DNA successively at every third nucleotide, allowing to excise an ICL from one strand through flanking incisions. Probably keeps excising with 3'-flap annealing until it reaches and unhooks the ICL (PubMed:25430771). Acts at sites that have a 5'-terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3' flap (PubMed:25430771). Also has endonuclease activity toward 5'-flaps (PubMed:20603015, PubMed:20603016, PubMed:24981866). {ECO:0000269|PubMed:20603015, ECO:0000269|PubMed:20603016, ECO:0000269|PubMed:20603073, ECO:0000269|PubMed:20671156, ECO:0000269|PubMed:24981866, ECO:0000269|PubMed:25135477, ECO:0000269|PubMed:25430771}.
• Disease: DISEASE: Interstitial nephritis, karyomegalic (KMIN) [MIM:614817]: A rare kidney disease characterized by chronic tubulointerstitial nephritis associated with massively enlarged tubular epithelial cell nuclei. The clinical picture is associated with recurrent upper respiratory tract infections in addition to chronic kidney disease beginning in the third decade of life. {ECO:0000269|PubMed:22772369}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Schizophrenia and autism. Schizophrenia is a severe psychiatric disorder characterized by positive, negative, and cognitive symptoms, and it is associated with increased mortality and severely reduced fecundity. Autim is a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate mental retardation.Disease susceptibility may be associated with variations affecting the gene represented in this entry. {ECO:0000269|PubMed:24344280}.
• Pathway: Fanconi anemia pathway - Homo sapiens (human);Fanconi Anemia Pathway;DNA Repair;Fanconi anemia pathway (Consensus)

Recessive Scores

• pRec: 0.0867

Intolerance Scores

• rvis_EVS: 0.28
• rvis_percentile_EVS: 70.76

Haploinsufficiency Scores

• pHI: 0.104
• hipred: N
• hipred_score: 0.421
• ghis: 0.506

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.114

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fan1
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; liver/biliary system phenotype; renal/urinary system phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: double-strand break repair via homologous recombination;DNA repair;nucleotide-excision repair;nucleotide-excision repair, DNA incision;interstrand cross-link repair
• Cellular component: nucleus;nucleoplasm;cytosol;intercellular bridge
• Molecular function: magnesium ion binding;phosphodiesterase I activity;protein binding;5'-3' exonuclease activity;5'-flap endonuclease activity;flap-structured DNA binding;ubiquitin-dependent protein binding