GeneBe

RFWD3

protein-coding

ring finger and WD repeat domain 3, the group of Ring finger proteins|WD repeat domain containing|FA complementation groups

Gene summary

Enables MDM2/MDM4 family protein binding activity; p53 binding activity; and ubiquitin protein ligase activity. Involved in several processes, including DNA metabolic process; regulation of cell cycle phase transition; and response to ionizing radiation. Located in cytosol; nucleoplasm; and site of double-strand break. Implicated in Fanconi anemia complementation group W. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_018124.4

Inheritance

AR

ClinVar variants

P:4U:413B:188

Top phenotype

Fanconi anemia, complementation group W

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr16:74,621,399-74,666,877

External References & Databases

Ensembl (ENSG00000168411)NCBI Gene (55159)OMIM (614151)HGNC:25539GenCCUniProt (Q6PCD5)AlphaFoldClinVar (RFWD3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~45.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemia, complementation group WMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044325

Submitter: PanelApp Australia

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Fanconi anemia, complementation group WLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0044325

Submitter: Labcorp Genetics (formerly Invitae)

Tourette syndromeNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

Fanconi anemia, complementation group WLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044325

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group WAR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Renal

Intervention: Allergy/Immunology/Infectious; Cardiovascular; Endocrine; 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; Growth hormone insufficiency has been described, and awareness may allow early treatment; 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

Comments: Individuals with FA may manifest a variety of congenital malformations, and awareness may allow prompt detection and management

Refs: 20301575; 28691929Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFWD3 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 634
not specifiedTotal: 153
RFWD3-related disorderTotal: 24
Fanconi anemia, complementation group WTotal: 14
Fanconi anemiaTotal: 2
Primary ciliary dyskinesiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018124.4. 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
8
clinvar
155
clinvar
4
clinvar
 167
missense
1
clinvar
379
clinvar
27
clinvar
2
clinvar
 409
nonsense
14
clinvar
 14
start loss
1
clinvar
 1
frameshift
1
clinvar
2
clinvar
8
clinvar
 11
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total224131826605

Highest pathogenic variant AF is 0.000006570993

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_018124.4RefSeqNP_060594.312MANE Select
ENST00000361070.9EnsemblENSP00000354361.412MANE Select
NM_001370534.1RefSeqNP_001357463.112Standard
NM_001370535.1RefSeqNP_001357464.112Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • double-strand break repair via homologous recombination
  • cellular response to DNA damage stimulus
  • response to ionizing radiation
  • protein ubiquitination
  • chromosome breakage

Molecular Function

  • p53 binding
  • ubiquitin-protein transferase activity
  • protein binding
  • metal ion binding
  • MDM2/MDM4 family protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • PML body
  • site of double-strand break

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000361070
Coding exons
12
Length
45488
Individuals with no LoFs
125707
Homozygous LoFs
0
Heterozygous LoFs
40
Defined
125747
p
0.000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.8924724211.120.00002195038
Missense (PolyPhen)85106.680.796781269
Synonymous-2.662061631.260.000008541540
Loss of Function2.682240.40.5450.00000227423

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.000270.00027rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000190.00018rare
South Asian0.000260.00026rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657, PubMed:28575658). Plays a key role in RPA- mediated DNA damage signaling and repair (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657, PubMed:28575658, PubMed:28691929). Acts by mediating ubiquitination of the RPA complex (RPA1, RPA2 and RPA3 subunits) and RAD51 at stalled replication forks, leading to remove them from DNA damage sites and promote homologous recombination (PubMed:26474068, PubMed:28575657, PubMed:28575658). Also mediates the ubiquitination of p53/TP53 in the late response to DNA damage, and acts as a positive regulator of p53/TP53 stability, thereby regulating the G1/S DNA damage checkpoint (PubMed:20173098). May act by catalyzing the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:20173098). In response to ionizing radiation, interacts with MDM2 and enhances p53/TP53 ubiquitination, possibly by restricting MDM2 from extending polyubiquitin chains on ubiquitinated p53/TP53 (PubMed:20173098). {ECO:0000269|PubMed:20173098, ECO:0000269|PubMed:21504906, ECO:0000269|PubMed:21558276, ECO:0000269|PubMed:26474068, ECO:0000269|PubMed:28575657, ECO:0000269|PubMed:28575658, ECO:0000269|PubMed:28691929}.;
Disease
DISEASE: Fanconi anemia, complementation group W (FANCW) [MIM:617784]: A form of Fanconi anemia, 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:28575657, ECO:0000269|PubMed:28691929}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0713

Intolerance Scores

LoFtool
0.755
RVIS EVS
-0.55
RVIS percentile EVS
19.86

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.552

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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