FANCI

protein-coding

FA complementation group I, the group of FA complementation groups

Gene summary

The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group I. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

Previous symbols:

KIAA1794

MANE transcript

NM_001113378.2

Inheritance

ClinVar variants

P:289U:909B:499

Top phenotype

Fanconi anemia, complementation group I

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr15:89,243,945-89,317,261

External References & Databases

Ensembl (ENSG00000140525)

Transcript & Mutation Effects

hg38 • Region Span ~73.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemia complementation group ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012186

Submitter: Labcorp Genetics (formerly Invitae)

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

primary ovarian failureMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0005387

Submitter: PanelApp Australia

Fanconi anemia complementation group ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012186

Submitter: PanelApp Australia

Fanconi anemia complementation group IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012186

Submitter: G2P

Fanconi anemia complementation group IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012186

Submitter: ClinGen

Fanconi anemia (FA) is a disease of DNA repair characterized by bone marrow failure, increased risk for malignancy, short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies (PMID: 21701511;29051281). The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents such as diepoxybutane (DEB) and mitomycin C (MMC), and high frequency of chromosomal aberrations. FANCD2 and FANCI form a protein complex (ID complex), their monoubiquitination is codependent and requires the FA core complex. FANCI was first reported in relation to autosomal recessive Fanconi anemia complementation group I in 2007 [Dorsman JC et al., PMID: 17452773]. The genetic evidence provided here stems from three Fanconi anemia patient cohorts [PMID: 26590883, 17460694 and 17452773]. These patients are either homozygous or compound heterozygous for pathogenetic FANCI variants. Lymphoblasts from these patients showed absence or weak expression of FANCI protein, absence of FANCD2 monoubiquitination and hypersensitivity to mitomycin (MMC) exposure [PMID: 17452773]. Fanci mouse models (Fanci +/- and Fanci -/-) showed FA features such as delayed development in utero, microphthalmia, cellular sensitivity to mitomycin C, occasional limb abnormalities and hematological deficiencies. Embryonic lethality in Fanci -/- mice was observed (PMID: 31219578). Functional studies include extensive evidence of absent FANCD2 monoubiquitination and MMC hypersensitivity from FA patients’ lymphoblasts and from HeLa with FANCI specific siRNA transfection [PMID: 17460694]. In summary, FANCI is definitively associated with FA complementation group I. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Fanconi anemia complementation group IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012186

Submitter: Natera

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group IAR

Manifestation: Audiologic/Otolaryngologic; Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal

Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Oncologic

Rationale: Specific treatments can help manifestations (eg, oral androgens for blood counts; G-CSF for neutrophil count); HSCT can be curative, but solid tumor risk may remain; Surveillance for complications such as bone marrow failure is recommended; Fanconi anemia can involve congenital cardiac (and other) anomalies, and awareness may allow early management

Refs: 14630800; 17452773; 17460694; 17412408; 20301575; 21568838

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FANCI variants in ClinVar

17 Conditions Cataloged

Fanconi anemiaTotal: 1921

Fanconi anemia complementation group ITotal: 607

not providedTotal: 287

not specifiedTotal: 177

Inborn genetic diseasesTotal: 133

FANCI-related disorderTotal: 56

FANCI-related disordersTotal: 13

Fanconi anemia complementation group ATotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001113378.2. 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			11 clinvar	463 clinvar	4 clinvar	478
missense	4 clinvar	3 clinvar	880 clinvar	28 clinvar	3 clinvar	918
nonsense	30 clinvar	46 clinvar	2 clinvar			78
start loss	1 clinvar		2 clinvar			3
frameshift	52 clinvar	82 clinvar	3 clinvar			137
splice donor/acceptor (+/-2bp)	3 clinvar	68 clinvar	11 clinvar	1 clinvar		83
Total	90	199	909	492	7	1697

Highest pathogenic variant AF is 0.00012020229

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 193 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001113378.2	RefSeq	NP_001106849.1	37	MANE Select
ENST00000310775.12	Ensembl	ENSP00000310842.8	37	MANE Select
NM_001376910.1	RefSeq	NP_001363839.1	35	Standard
NM_001376911.1	RefSeq	NP_001363840.1	37	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
Gastric Cancer Network 2
TP53 Regulates Transcription of DNA Repair Genes
Fanconi Anemia Pathway
DNA Repair

Biological Process

cell cycle
positive regulation of protein ubiquitination
interstrand cross-link repair

Molecular Function

DNA binding
protein binding
DNA polymerase binding

Cellular Component

nucleoplasm
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310775
Coding exons: 37
Length: 73313
Individuals with no LoFs: 125498
Homozygous LoFs: 0
Heterozygous LoFs: 250
Defined: 125748
p: 0.000995

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.35	747	650	1.15	0.0000325	8740
Missense (PolyPhen)		114	118.33	0.96338		1739
Synonymous	-1.78	274	239	1.15	0.0000127	2471
Loss of Function	1.37	63	75.9	0.830	0.00000377	971

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00092	0.00092	rare
Latino/Admixed American	0.00089	0.00087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00083	0.00082	rare
Finnish	0.0034	0.0034	notable
European (Non-Finnish)	0.00063	0.00063	rare
South Asian	0.0012	0.0012	notable
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an essential role in the repair of DNA double- strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA repair sites. Required for maintenance of chromosomal stability. Specifically binds branched DNA: binds both single- stranded DNA (ssDNA) and double-stranded DNA (dsDNA). Participates in S phase and G2 phase checkpoint activation upon DNA damage. {ECO:0000269|PubMed:17412408, ECO:0000269|PubMed:17452773, ECO:0000269|PubMed:17460694, ECO:0000269|PubMed:19111657}.;
Disease: DISEASE: Fanconi anemia complementation group I (FANCI) [MIM:609053]: A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. {ECO:0000269|PubMed:17412408, ECO:0000269|PubMed:17452773, ECO:0000269|PubMed:17460694}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.203

Intolerance Scores

LoFtool: 0.265
RVIS EVS: -0.12
RVIS percentile EVS: 44.54

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.747

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High