GeneBe

FANCA

protein-coding

FA complementation group A, the group of FA core complex|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 A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

Previous symbols:
  • FACA
  • FANCH

MANE transcript

NM_000135.4

Inheritance

AR

ClinVar variants

P:983U:2584B:1594

Top phenotype

Fanconi anemia, complementation group A

gnomAD constraint

pLI —, LoF o/e 1.15

Max pathogenic AF

—

Genomic locus

chr16:89,726,683-89,816,977

External References & Databases

Ensembl (ENSG00000187741)NCBI Gene (2175)OMIM (607139)HGNC:3582GenCCUniProt (O15360)AlphaFoldClinVar (FANCA)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~90.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemia complementation group ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009215

Submitter: Myriad Women's Health

Fanconi anemia complementation group ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009215

Submitter: G2P

Fanconi anemia complementation group ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009215

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Fanconi anemia complementation group ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009215

Submitter: Labcorp Genetics (formerly Invitae)

Fanconi anemia complementation group ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009215

Submitter: Ambry Genetics

Fanconi anemia complementation group ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009215

Submitter: ClinGen

There is abundant evidence published associating the FANCA gene with Fanconi anemia complementation group A, since the gene-disease relationship was first proposed by Fanconi Anaemia/Breast Cancer Consortium (1996). Multiple case level studies have been performed with FA patients that have variants in the FANCA gene. Eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) are part of a nuclear multiprotein core complex which triggers activating monoubiquitination of the FANCD2 in the FA/BRCA DNA repair pathway. Multiple Fanca deficient mouse models have been established to show consistent phenotypes with FA patients including growth retardation, microphthalmia, craniofacial malformations, and hypogonadism. All of these types of evidence are consistent with a definitive relationship between the FANCA gene and Fanconi anemia complementation group A.

Fanconi anemia complementation group ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009215

Submitter: PanelApp Australia

Fanconi anemia complementation group ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009215

Submitter: Natera

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group AAR

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: 13826667; 6338978; 2571931; 1536187; 1521091; 8502512; 8081006; 8781414; 9371798; 10094191; 11389461; 14504102; 14605744; 17105750; 20301575; 20507306; 21273304; 22480464; 22950077; 23067021; 23898106; 23973728Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FANCA variants in ClinVar

20 Conditions Cataloged
Fanconi anemiaTotal: 4441
Inborn genetic diseasesTotal: 2599
Fanconi anemia complementation group ATotal: 1566
not providedTotal: 880
not specifiedTotal: 255
FANCA-related disorderTotal: 201
Ovarian cancerTotal: 10
Hereditary cancer-predisposing syndromeTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000135.4. 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.

EffectPLPVUSLBBSum
synonymous
5
clinvar
2
clinvar
43
clinvar
1354
clinvar
6
clinvar
 1410
missense
32
clinvar
79
clinvar
2508
clinvar
229
clinvar
4
clinvar
 2852
nonsense
127
clinvar
108
clinvar
5
clinvar
 240
start loss
4
clinvar
6
clinvar
 10
frameshift
211
clinvar
158
clinvar
10
clinvar
 379
splice donor/acceptor (+/-2bp)
83
clinvar
168
clinvar
18
clinvar
1
clinvar
 270
Total46252125841584105161

Highest pathogenic variant AF is 0.00012729385

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000135.4RefSeqNP_000126.243MANE Select
ENST00000389301.8EnsemblENSP00000373952.343MANE Select
NM_001018112.3RefSeqNP_001018122.111Standard
NM_001286167.3RefSeqNP_001273096.143Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Fanconi anemia pathway - Homo sapiens (human)
  • Fanconi Anemia Pathway
  • DNA Repair
  • role of brca1 brca2 and atr in cancer susceptibility
  • brca1 dependent ub ligase activity

Biological Process

  • DNA repair
  • male meiotic nuclear division
  • male gonad development
  • female gonad development
  • interstrand cross-link repair

Molecular Function

  • protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • Fanconi anaemia nuclear complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000389301
Coding exons
43
Length
79109
Individuals with no LoFs
125478
Homozygous LoFs
0
Heterozygous LoFs
270
Defined
125748
p
0.00107
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-5.4112027771.550.00004829398
Missense (PolyPhen)4131.2811.3107289
Synonymous-8.035063221.570.00002182907
Loss of Function-1.299683.31.150.00000424952

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00140.0014notable
Latino/Admixed American0.000980.00098rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.00150.0015notable
Finnish0.000190.00018rare
European (Non-Finnish)0.00130.0013notable
South Asian0.00110.0011notable
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function. May be involved in interstrand DNA cross-link repair and in the maintenance of normal chromosome stability.;
Disease
DISEASE: Fanconi anemia, complementation group A (FANCA) [MIM:227650]: 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:10094191, ECO:0000269|PubMed:10210316, ECO:0000269|PubMed:10521298, ECO:0000269|PubMed:10807541, ECO:0000269|PubMed:11091222, ECO:0000269|PubMed:17924555, ECO:0000269|PubMed:9371798, ECO:0000269|PubMed:9399890, ECO:0000269|PubMed:9929978}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.243

Intolerance Scores

LoFtool
0.0821
RVIS EVS
-0.1
RVIS percentile EVS
45.67

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.985

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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