FANCD2

protein-coding

FA complementation group D2, the group of FA complementation groups|Armadillo like helical domain containing

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 D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2) involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

Previous symbols:

FACD
FANCD

MANE transcript

NM_001018115.3

Inheritance

ClinVar variants

P:300U:713B:449

Top phenotype

Fanconi anemia, complementation group D2

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr3:10,026,370-10,101,932

External References & Databases

Ensembl (ENSG00000144554)

Transcript & Mutation Effects

hg38 • Region Span ~75.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Fanconi anemia complementation group D2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009214

Submitter: PanelApp Australia

Fanconi anemia complementation group D2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009214

Submitter: G2P

Fanconi anemia complementation group D2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009214

Submitter: Ambry Genetics

Fanconi anemia complementation group D2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009214

Submitter: Natera

Fanconi anemia complementation group D2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009214

Submitter: ClinGen

FANCD2 is one of the more than twenty Fanconi anemia (FA) or FA-like genes known to cause autosomal recessive Fanconi anemia characterized by bone marrow failure, developmental abnormalities, cellular hypersensitivity to DNA cross-linking agents such as mitomycin C and diepoxybutane, and cancer predisposition. Biallelic predicted and/or proven loss-of-function variants in FANCD2 were first identified in Fanconi anemia patients in 2001 (PMID: 11239453). Since then, more than 20 variants in FANCD2 have been reported in individuals with FA complementation group D2 (PMIDs: 17436244, 25703294, 23613520). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) for the variant type has been reached. Although most of the reported variants have a predicted and/or proven loss-of-function effect, the presence of residual FANCD2 protein has been documented in the individuals and cell models, regardless of the ‘reverse mosaicism’ phenomenon where hematopoietic cells may regain the wild-type allele via mechanisms such as reversing the mutation or recombination with gene conversion. This gene-disease relationship is further supported by functional studies demonstrating the protein-protein interactions with other FA genes, functional alteration in the patient fibroblast cells carrying biallelic FANCD2 variants, and rescue of the function in the patient cell culture models (PMID: 11239454). Animal studies demonstrated the recapitulation of the biochemical and morphological phenotypes reported in humans (PMIDs: 12893777, 14667412). In summary, FANCD2 is definitively associated with FA complementation group D2. This has been repeatedly demonstrated in the research and clinical diagnostic settings and upheld over time.

Fanconi anemia complementation group D2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009214

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group D2AR

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: 17436244; 20301575; 22720145; 23285130

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FANCD2 variants in ClinVar

27 Conditions Cataloged

Fanconi anemiaTotal: 1578

Fanconi anemia complementation group D2Total: 569

not providedTotal: 271

not specifiedTotal: 194

Inborn genetic diseasesTotal: 126

FANCD2-related disorderTotal: 75

Hereditary breast ovarian cancer syndromeTotal: 50

FANCD2-related disordersTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001018115.3. 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			18 clinvar	402 clinvar	4 clinvar	424
missense	4 clinvar	12 clinvar	680 clinvar	41 clinvar	1 clinvar	738
nonsense	32 clinvar	49 clinvar	3 clinvar			84
start loss			1 clinvar			1
frameshift	58 clinvar	62 clinvar	3 clinvar			123
splice donor/acceptor (+/-2bp)	7 clinvar	76 clinvar	8 clinvar	1 clinvar		92
Total	101	199	713	444	5	1462

Highest pathogenic variant AF is 0.0003904112

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001018115.3	RefSeq	NP_001018125.1	43	MANE Select
ENST00000675286.1	Ensembl	ENSP00000502379.1	43	MANE Select
NM_001319984.2	RefSeq	NP_001306913.1	43	Standard
NM_001374253.1	RefSeq	NP_001361182.1	42	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
miRNA Regulation of DNA Damage Response
TP53 Regulates Transcription of DNA Repair Genes
DNA Damage Response
Fanconi Anemia Pathway

Biological Process

DNA repair
synapsis
gamete generation
response to gamma radiation
cellular response to oxidative stress

Molecular Function

protein binding
DNA polymerase binding

Cellular Component

condensed chromosome
nucleus
nucleoplasm
nucleolus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000287647
Coding exons: 42
Length: 75517
Individuals with no LoFs: 125570
Homozygous LoFs: 0
Heterozygous LoFs: 178
Defined: 125748
p: 0.000708

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0373	735	738	0.996	0.0000377	9656
Missense (PolyPhen)		162	206.82	0.78327		2871
Synonymous	0.529	264	275	0.959	0.0000144	2737
Loss of Function	2.42	60	83.9	0.715	0.00000439	1022

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0014	0.0014	notable
Latino/Admixed American	0.00072	0.00072	rare
Ashkenazi Jewish	0.00069	0.00069	rare
East Asian	0.00065	0.00065	rare
Finnish	0.00056	0.00055	rare
European (Non-Finnish)	0.00069	0.00069	rare
South Asian	0.00052	0.00052	rare
Other	0.00081	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for maintenance of chromosomal stability. Promotes accurate and efficient pairing of homologs during meiosis. Involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing. May participate in S phase and G2 phase checkpoint activation upon DNA damage. Plays a role in preventing breakage and loss of missegregating chromatin at the end of cell division, particularly after replication stress. Required for the targeting, or stabilization, of BLM to non-centromeric abnormal structures induced by replicative stress. Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be involved in B-cell immunoglobulin isotype switching. {ECO:0000269|PubMed:11239453, ECO:0000269|PubMed:11239454, ECO:0000269|PubMed:12086603, ECO:0000269|PubMed:12239151, ECO:0000269|PubMed:14517836, ECO:0000269|PubMed:15115758, ECO:0000269|PubMed:15314022, ECO:0000269|PubMed:15377654, ECO:0000269|PubMed:15454491, ECO:0000269|PubMed:15650050, ECO:0000269|PubMed:15661754, ECO:0000269|PubMed:15671039, ECO:0000269|PubMed:19465921}.;
Disease: DISEASE: Fanconi anemia complementation group D2 (FANCD2) [MIM:227646]: 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:11239453}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.989
RVIS EVS: -0.92
RVIS percentile EVS: 9.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.928

Gene Damage Prediction

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