RFWD3

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

Basic information

Region (hg38): 16:74621398-74666877

Links

ENSG00000168411 ∙ NCBI:55159 ∙ OMIM:614151 ∙ HGNC:25539 ∙ Uniprot:Q6PCD5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Tourette syndrome (No Known Disease Relationship), mode of inheritance: Unknown
• Fanconi anemia (Supportive), mode of inheritance: AR
• Fanconi anemia, complementation group W (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Fanconi anemia, complementation group W	AR	Allergy/Immunology/Infectious; Cardiovascular; Endocrine; Hematologic; Oncologic	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	Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Renal	20301575; 28691929
Individuals with FA may manifest a variety of congenital malformations, and awareness may allow prompt detection and management

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RFWD3 gene.

• not provided (290 variants)
• Inborn genetic diseases (36 variants)
• Fanconi anemia, complementation group W (8 variants)
• not specified (2 variants)
• RFWD3-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RFWD3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	70	10	81
missense			159	9	6	174
nonsense			2			2
start loss						0
frameshift			3			3
inframe indel			3			3
splice donor/acceptor (+/-2bp)			2			2
splice region			6	9	1	16
non coding			3	25	6	34
Total	0	0	173	104	22

Variants in RFWD3

This is a list of pathogenic ClinVar variants found in the RFWD3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-74623931-C-T			Likely benign (Jul 06, 2023)
16-74623934-C-T			Uncertain significance (Jun 18, 2022)
16-74623940-A-G			Likely benign (Sep 25, 2022)
16-74623941-T-A			Uncertain significance (Jun 18, 2022)
16-74623941-T-C			Uncertain significance (Nov 30, 2022)
16-74623946-G-A			Likely benign (Feb 27, 2022)
16-74623954-T-C		RFWD3-related disorder	Likely benign (Jan 22, 2024)
16-74623967-G-T			Likely benign (Aug 07, 2023)
16-74623972-C-T			Uncertain significance (Aug 20, 2022)
16-74623977-T-C			Uncertain significance (Dec 06, 2022)
16-74623986-C-T			Uncertain significance (Oct 13, 2023)
16-74623987-G-A		RFWD3-related disorder • not specified	Conflicting classifications of pathogenicity (Dec 28, 2023)
16-74623987-G-T			Uncertain significance (May 28, 2023)
16-74623992-A-G			Uncertain significance (Jan 23, 2022)
16-74623998-A-G			Uncertain significance (Mar 14, 2022)
16-74624006-G-A			Likely benign (Jan 12, 2024)
16-74624008-T-C			Uncertain significance (Jul 19, 2022)
16-74624009-G-A			Likely benign (Oct 17, 2023)
16-74624015-C-T			Benign (Jan 16, 2024)
16-74624026-C-T			Uncertain significance (Feb 18, 2022)
16-74624027-G-A			Likely benign (Nov 27, 2023)
16-74624030-C-G		not specified	Uncertain significance (Jan 07, 2023)
16-74624048-C-T		Fanconi anemia, complementation group W	Likely benign (Jun 14, 2023)
16-74624049-G-C			Uncertain significance (Nov 28, 2023)
16-74624058-G-C			Uncertain significance (Apr 24, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RFWD3	protein_coding	protein_coding	ENST00000361070	12	45488

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.53e-10	0.996	125707	0	40	125747	0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.892	472	421	1.12	0.0000219	5038
Missense in Polyphen		85	106.68	0.79678		1269
Synonymous	-2.66	206	163	1.26	0.00000854	1540
Loss of Function	2.68	22	40.4	0.545	0.00000227	423

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000275	0.000275
Ashkenazi Jewish	0.00	0.00
East Asian	0.000272	0.000272
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000186	0.000185
Middle Eastern	0.000272	0.000272
South Asian	0.000262	0.000261
Other	0.00	0.00

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.0967
• hipred: Y
• hipred_score: 0.697
• ghis: 0.599

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.552

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rfwd3
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; cellular phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: double-strand break repair via homologous recombination;cellular response to DNA damage stimulus;response to ionizing radiation;protein ubiquitination;chromosome breakage;replication fork processing;mitotic G1 DNA damage checkpoint;interstrand cross-link repair;regulation of DNA damage checkpoint
• Cellular component: nucleus;nucleoplasm;cytoplasm;PML body;site of double-strand break;site of DNA damage
• Molecular function: p53 binding;ubiquitin-protein transferase activity;protein binding;metal ion binding;MDM2/MDM4 family protein binding