FANCG

protein-coding

FA complementation group G, 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 G. [provided by RefSeq, Jul 2008]

Previous symbols:

XRCC9

MANE transcript

NM_004629.2

Inheritance

ClinVar variants

P:217U:638B:451

Top phenotype

Fanconi anemia, complementation group G

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr9:35,073,835-35,080,004

External References & Databases

Ensembl (ENSG00000221829)

Transcript & Mutation Effects

hg38 • Region Span ~6.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemia complementation group GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013565

Submitter: G2P

Fanconi anemia complementation group GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013565

Submitter: ClinGen

There is abundant evidence published associating the FANCG gene with Fanconi anemia complementation group G, since the gene-disease relationship was first proposed by de Winter et al. (1998). Multiple case level studies have been performed with FA patients that have variants in the FANCG 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 Fancg deficient mouse models have been established to show consistent phenotypes with FA patients including impaired fertility, chromosome breakage and cross linker sensitivity, and spontaneous hematologic sequelae. All of these types of evidence are consistent with a definitive relationship between the FANCG gene and Fanconi anemia complementation group G.

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Fanconi anemia complementation group GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013565

Submitter: PanelApp Australia

Fanconi anemia complementation group GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013565

Submitter: Labcorp Genetics (formerly Invitae)

Fanconi anemia complementation group GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013565

Submitter: Natera

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group GAR

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: 9806548; 20301575

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FANCG variants in ClinVar

12 Conditions Cataloged

Fanconi anemiaTotal: 877

Inborn genetic diseasesTotal: 718

Fanconi anemia complementation group GTotal: 371

not providedTotal: 86

not specifiedTotal: 43

FANCG-related disorderTotal: 21

Ovarian cancerTotal: 8

Fanconi anemia complementation group ATotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004629.2. 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	2 clinvar	2 clinvar	15 clinvar	407 clinvar		426
missense	4 clinvar	6 clinvar	612 clinvar	41 clinvar	3 clinvar	666
nonsense	29 clinvar	28 clinvar	1 clinvar			58
start loss		2 clinvar				2
frameshift	41 clinvar	58 clinvar	6 clinvar			105
splice donor/acceptor (+/-2bp)	8 clinvar	37 clinvar	4 clinvar			49
Total	84	133	638	448	3	1306

Highest pathogenic variant AF is 0.000066994115

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004629.2	RefSeq	NP_004620.1	14	MANE Select
ENST00000378643.8	Ensembl	ENSP00000367910.4	14	MANE Select
ENST00000425676.5	Ensembl	ENSP00000412793.1	4	Standard
ENST00000448890.2	Ensembl	ENSP00000409607.2	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
Retinoblastoma (RB) in Cancer
Fanconi Anemia Pathway
DNA Repair
role of brca1 brca2 and atr in cancer susceptibility

Biological Process

ovarian follicle development
DNA repair
mitochondrion organization
spermatid development
response to radiation

Molecular Function

damaged DNA binding
protein binding

Cellular Component

nucleoplasm
nucleolus
mitochondrion
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378643
Coding exons: 14
Length: 6182
Individuals with no LoFs: 125638
Homozygous LoFs: 0
Heterozygous LoFs: 110
Defined: 125748
p: 0.000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.245	301	313	0.961	0.0000182	3934
Missense (PolyPhen)		83	84.734	0.97954		1149
Synonymous	0.00585	138	138	0.999	0.00000740	1348
Loss of Function	1.15	25	32.0	0.781	0.00000151	366

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00043	0.00044	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00060	0.00058	rare
South Asian	0.00039	0.00039	rare
Other	0.00066	0.00065	rare

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 implicated in interstrand DNA cross-link repair and in the maintenance of normal chromosome stability. Candidate tumor suppressor gene.;

Recessive Scores

pRec: 0.406

Intolerance Scores

LoFtool: 0.873
RVIS EVS: 0.78
RVIS percentile EVS: 87.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.767

Gene Damage Prediction

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