RFWD3

Summary

RFWD3 (ring finger and WD repeat domain 3, HGNC:25539) is a protein-coding gene on chromosome 16q23.1, encoding E3 ubiquitin-protein ligase RFWD3 (Q6PCD5). E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage. It is a selective cancer dependency (DepMap: 14.7% of cell lines).

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 nucleoplasm and site of double-strand break. Implicated in Fanconi anemia complementation group W.

Source: NCBI Gene 55159 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fanconi anemia, complementation group W (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 725 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 119
• Cancer dependency (DepMap): dependent in 14.7% of screened cell lines
• MANE Select transcript: NM_018124

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25539
Approved symbol	RFWD3
Name	ring finger and WD repeat domain 3
Location	16q23.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10520, RNF201, FANCW
Ensembl gene	ENSG00000168411
Ensembl biotype	protein_coding
OMIM	614151
Entrez	55159

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 6 retained_intron

ENST00000361070, ENST00000571750, ENST00000571776, ENST00000572337, ENST00000572610, ENST00000572840, ENST00000572990, ENST00000575113, ENST00000575154, ENST00000575281, ENST00000575397, ENST00000576652, ENST00000888023, ENST00000938436, ENST00000938437, ENST00000938438, ENST00000938439, ENST00000938440, ENST00000938441, ENST00000938442, ENST00000938443

RefSeq mRNA: 9 — MANE Select: NM_018124 NM_001370534, NM_001370535, NM_001370536, NM_001370537, NM_001370539, NM_001370540, NM_001370542, NM_001370543, NM_018124

CCDS: CCDS32486

Canonical transcript exons

ENST00000361070 — 13 exons

Exon	Start	End
ENSE00001176233	74626343	74626554
ENSE00001176241	74628452	74628666
ENSE00001176263	74632523	74632673
ENSE00001176271	74636346	74636577
ENSE00001176290	74637856	74637970
ENSE00001379090	74666786	74666877
ENSE00001390849	74660932	74661451
ENSE00002636247	74621399	74624071
ENSE00003476962	74644362	74644453
ENSE00003497228	74651920	74652122
ENSE00003521183	74630781	74630957
ENSE00003562924	74644541	74644735
ENSE00003576237	74649132	74649202

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 94.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.7454 / max 248.7903, expressed in 1801 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158116	25.7454	1801

Top tissues by expression

273 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	94.02	gold quality
secondary oocyte	CL:0000655	93.40	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.74	gold quality
ventricular zone	UBERON:0003053	87.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.10	gold quality
ganglionic eminence	UBERON:0004023	85.34	gold quality
bone marrow cell	CL:0002092	84.64	gold quality
embryo	UBERON:0000922	84.33	gold quality
right testis	UBERON:0004534	84.18	gold quality
testis	UBERON:0000473	84.09	gold quality
stromal cell of endometrium	CL:0002255	83.06	gold quality
bone marrow	UBERON:0002371	82.94	gold quality
left testis	UBERON:0004533	82.83	gold quality
lymph node	UBERON:0000029	82.05	gold quality
rectum	UBERON:0001052	82.05	gold quality
buccal mucosa cell	CL:0002336	81.97	gold quality
colonic epithelium	UBERON:0000397	81.44	gold quality
lower esophagus mucosa	UBERON:0035834	80.78	gold quality
islet of Langerhans	UBERON:0000006	80.77	gold quality
granulocyte	CL:0000094	80.60	gold quality
monocyte	CL:0000576	80.48	gold quality
esophagus mucosa	UBERON:0002469	80.46	gold quality
leukocyte	CL:0000738	80.37	gold quality
adrenal tissue	UBERON:0018303	80.30	gold quality
mononuclear cell	CL:0000842	80.20	gold quality
tonsil	UBERON:0002372	79.88	gold quality
skin of leg	UBERON:0001511	79.80	gold quality
skin of abdomen	UBERON:0001416	79.66	gold quality
vermiform appendix	UBERON:0001154	79.62	gold quality
gall bladder	UBERON:0002110	79.28	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

100 targeting RFWD3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8087	99.90	69.55	1351

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 14.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 14)

• Study identifies RFWD3 as a positive regulator of p53 stability when the G(1) cell cycle checkpoint is activated and provides an explanation for how p53 is protected from degradation in the presence of high levels of Mdm2. (PMID:20173098)
• RFWD3 and RPA2 functionally interact and participate in replication checkpoint control (PMID:21504906)
• RFWD3 is recruited to sites of DNA damage and facilitates RPA-mediated DNA damage signaling and repair (PMID:21558276)
• RFWD3-dependent ubiquitination of RPA regulates repair at stalled replication forks. (PMID:26474068)
• Single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit interstrand crossling repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. (PMID:28575657)
• E3 ligase RFWD3 functions in timely removal and degradation of RPA and RAD51 to allow homologous recombination progression to subsequent steps following mitomycin C damage. (PMID:28575658)
• The results suggest that RPA phosphorylation enhances the recruitment of PRP19 to RPA-ssDNA and stimulates RPA ubiquitylation through a process requiring both PRP19 and RFWD3, thereby triggering a phosphorylation-ubiquitylation circuitry that promotes ATR activation and homologous recombination. (PMID:28666352)
• Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer. (PMID:31571161)
• E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells. (PMID:32391871)
• Down-regulation of RFWD3 inhibits cancer cells proliferation and migration in gastric carcinoma. (PMID:32902405)
• The E3 ligase RFWD3 stabilizes ORC in a p53-dependent manner. (PMID:33044890)
• The ubiquitin ligase RFWD3 is required for translesion DNA synthesis. (PMID:33321094)
• Systematic analysis on expression quantitative trait loci identifies a novel regulatory variant in ring finger and WD repeat domain 3 associated with prognosis of pancreatic cancer. (PMID:35830250)
• RFWD3 promotes ZRANB3 recruitment to regulate the remodeling of stalled replication forks. (PMID:37036693)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	rfwd3	ENSDARG00000087752
mus_musculus	Rfwd3	ENSMUSG00000033596
rattus_norvegicus	Rfwd3	ENSRNOG00000051461
drosophila_melanogaster	CG17329	FBGN0028896
drosophila_melanogaster	CG14983	FBGN0035479
drosophila_melanogaster	CG13481	FBGN0036421
drosophila_melanogaster	CG31807	FBGN0051807
drosophila_melanogaster	CG33552	FBGN0053552
drosophila_melanogaster	mus302	FBGN0287696

Protein

Protein identifiers

E3 ubiquitin-protein ligase RFWD3 — Q6PCD5 (reviewed: Q6PCD5)

Alternative names: RING finger and WD repeat domain-containing protein 3, RING finger protein 201

All UniProt accessions (5): Q6PCD5, I3L284, I3L299, I3L2T2, I3L4I5

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage. Plays a key role in RPA-mediated DNA damage signaling and repair. 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. 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. May act by catalyzing the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome. 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. Required to translesion DNA synthesis across DNA-protein cross-link adducts by catalyzing ubiquitination of proteins on single-stranded DNA (ssDNA).

Subunit / interactions. Interacts with MDM2 and p53/TP53. Binds to the RPA complex via direct interaction with RPA2. Interacts with RAD51.

Subcellular location. Nucleus. PML body. Cytoplasm.

Post-translational modifications. Phosphorylated at Ser-46 and Ser-63 upon DNA damage by ATM or ATR. ATM phosphorylation occurs at early times upon DNA damage, while ATR is the major kinase at later times. Phosphorylation by ATM and ATR is required to stabilize p53/TP53. Part of the phosphorylation depends upon RPA2 presence.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The coiled coil domain may be involved in RPA2-binding.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (9): NP_001357463, NP_001357464, NP_001357465, NP_001357466, NP_001357468, NP_001357469, NP_001357471, NP_001357472, NP_060594* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR037381	RFWD3	Family
IPR056527	WD40_RFWD3	Domain

Pfam: PF13639, PF23419

UniProt features (69 total): strand 31, mutagenesis site 9, turn 6, sequence variant 5, sequence conflict 4, repeat 3, compositionally biased region 3, region of interest 3, modified residue 2, chain 1, zinc finger region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6CVZ	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PCD5-F1	70.95	0.47

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 46, 63

Mutagenesis-validated functional residues (9):

Position	Phenotype
36–38	decreased interaction with rad51; when associated with 53-a–a-55 and 70-a–a-72.
46	markedly decreases phosphorylation following ionizing radiation and abolishes ability to stimulate p53/tp53 ubiquitinati
53–55	decreased interaction with rad51; when associated with 36-a–a-38 and 70-a–a-72.
63	markedly decreases phosphorylation following ionizing radiation and abolishes ability to stimulate p53/tp53 ubiquitinati
70–72	decreased interaction with rad51; when associated with 36-a–a-38 and 53-a–a-55.
315	abolishes ability to stimulate p53/tp53 ubiquitination. no effect on nuclear localization in response to dna damage.
499	does not affect interaction with the rpa complex and subsequent recruitment at dna damage sites.
518	does not affect interaction with the rpa complex and subsequent recruitment at dna damage sites.
543	abolishes interaction with the rpa complex and subsequent recruitment at dna damage sites.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 432 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_RESPONSE_TO_IONIZING_RADIATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CELL_CYCLE_PHASE_TRANSITION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE_G1_S_PHASE_TRANSITION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_CELL_CYCLE_G1_S_PHASE_TRANSITION, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_NEGATIVE_REGULATION_OF_MITOTIC_CELL_CYCLE

GO Biological Process (9): double-strand break repair via homologous recombination (GO:0000724), DNA damage response (GO:0006974), response to ionizing radiation (GO:0010212), protein ubiquitination (GO:0016567), replication fork processing (GO:0031297), mitotic G1 DNA damage checkpoint signaling (GO:0031571), interstrand cross-link repair (GO:0036297), regulation of DNA damage checkpoint (GO:2000001), DNA repair (GO:0006281)

GO Molecular Function (8): p53 binding (GO:0002039), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), MDM2/MDM4 family protein binding (GO:0097371), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), PML body (GO:0016605), site of DNA damage (GO:0090734), site of double-strand break (GO:0035861)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein binding	2
recombinational repair	1
double-strand break repair	1
cellular response to stress	1
response to radiation	1
protein modification by small protein conjugation	1
DNA-templated DNA replication maintenance of fidelity	1
mitotic G1 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G1/S transition checkpoint signaling	1
DNA repair	1
DNA damage checkpoint signaling	1
regulation of cellular response to stress	1
regulation of cell cycle checkpoint	1
DNA metabolic process	1
DNA damage response	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear body	1
chromosome	1
site of DNA damage	1

Protein interactions and networks

STRING

1034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RFWD3	MDM2	Q00987	719
RFWD3	FANCD2	Q9BXW9	669
RFWD3	FANCM	Q8IYD8	651
RFWD3	ERCC4	Q92889	644
RFWD3	FANCA	O15360	644
RFWD3	FANCI	Q9NVI1	641
RFWD3	UBE2T	Q9NPD8	631
RFWD3	FANCB	Q8NB91	620
RFWD3	MAD2L2	Q9UI95	609
RFWD3	SLX4	Q8IY92	609
RFWD3	RAD51C	O43502	602
RFWD3	RAD51	Q06609	602
RFWD3	BRIP1	Q9BX63	599
RFWD3	FANCL	Q9NW38	599
RFWD3	FANCG	O15287	598

IntAct

86 interactions, top by confidence:

A	B	Type	Score
TP53	MDM2	psi-mi:“MI:0914”(association)	1.000
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
RPA1	RPA2	psi-mi:“MI:0914”(association)	0.960
RPA3	RPA2	psi-mi:“MI:0914”(association)	0.930
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
RFWD3	RPA2	psi-mi:“MI:0915”(physical association)	0.700
RFWD3	RPA2	psi-mi:“MI:0403”(colocalization)	0.700
CCT5	TXNDC9	psi-mi:“MI:0914”(association)	0.640
RFWD3	TP53	psi-mi:“MI:0914”(association)	0.620
RFWD3	TP53	psi-mi:“MI:0407”(direct interaction)	0.620
RFWD3	TP53	psi-mi:“MI:0915”(physical association)	0.620
RFWD3	MDM2	psi-mi:“MI:0915”(physical association)	0.590
RFWD3	MDM2	psi-mi:“MI:0407”(direct interaction)	0.590
RFWD3	UBE2N	psi-mi:“MI:0915”(physical association)	0.590
RFWD3	UBE2D1	psi-mi:“MI:0915”(physical association)	0.550
RFWD3	UBE2D2	psi-mi:“MI:0915”(physical association)	0.550
UBE2D3	RFWD3	psi-mi:“MI:0915”(physical association)	0.550
UBE2D4	RFWD3	psi-mi:“MI:0915”(physical association)	0.550
UBE2D2	RFWD3	psi-mi:“MI:0915”(physical association)	0.550
RFWD3	UBE2D3	psi-mi:“MI:0915”(physical association)	0.550
PIP4K2A	AP3B1	psi-mi:“MI:0914”(association)	0.530
CEP170	DAPK3	psi-mi:“MI:0914”(association)	0.530
TPH1	YEATS4	psi-mi:“MI:0914”(association)	0.530

BioGRID (147): RFWD3 (Affinity Capture-RNA), RFWD3 (Affinity Capture-RNA), RFWD3 (Affinity Capture-MS), RFWD3 (Affinity Capture-MS), RFWD3 (Affinity Capture-MS), RFWD3 (Synthetic Lethality), RFWD3 (Affinity Capture-MS), CANX (Affinity Capture-MS), CCT6A (Affinity Capture-MS), GLG1 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), MBNL1 (Affinity Capture-MS), PFDN1 (Affinity Capture-MS), PFDN2 (Affinity Capture-MS), TCP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GLK3, A0A974CYQ5, A2AHJ4, A5WW08, D2HNY3, D2HWM5, E7F6T8, F1ND48, O15040, O70260, O95071, P59328, Q3TLR7, Q4V837, Q58DC2, Q58WW2, Q5E9J6, Q5F479, Q5FWP4, Q5NVC7, Q5R9B8, Q5RF77, Q5RGA4, Q5RHI5, Q5ZLG9, Q62671, Q66JG1, Q6DDH2, Q6P1W0, Q6P256, Q6PCD5, Q6PJI9, Q6RI45, Q80TP3, Q80U93, Q810L3, Q8C0M0, Q8CBW4, Q8CIK8, Q8CIN9

Diamond homologs: A0A1L8GLK3, A0A974CYQ5, D2HWM5, Q6PCD5, Q8CIK8, O64425, Q6FWF3, Q8SV35, Q9SI09

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RFWD3	ubiquitination
RFWD3	“up-regulates quantity by stabilization”	TP53	ubiquitination
RFWD3	“up-regulates activity”	MDM2	binding
RFWD3	“up-regulates activity”	RAD51	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TICAM1, RIP1-mediated IKK complex recruitment	5	56.7×	3e-06
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	7	48.6×	3e-08
IKK complex recruitment mediated by RIP1	5	46.8×	7e-06
Recognition of DNA damage by PCNA-containing replication complex	5	35.9×	2e-05
HSF1 activation	5	35.9×	2e-05
Formation of Incision Complex in GG-NER	5	23.9×	7e-05
E3 ubiquitin ligases ubiquitinate target proteins	6	21.9×	2e-05
Regulation of TP53 Activity through Phosphorylation	8	17.8×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein monoubiquitination	6	30.8×	1e-05
protein polyubiquitination	9	15.5×	3e-06
protein K48-linked ubiquitination	6	15.1×	4e-04
ubiquitin-dependent protein catabolic process	9	10.0×	5e-05
protein folding	6	9.3×	2e-03
regulation of cell cycle	6	6.7×	8e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	8	6.2×	2e-03
protein ubiquitination	8	4.9×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

725 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	436
Likely benign	236
Benign	20

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
446412	NM_018124.4(RFWD3):c.1916T>A (p.Ile639Lys)	Pathogenic
929582	NM_018124.4(RFWD3):c.205_206dup (p.Leu70fs)	Pathogenic
3780547	NM_018124.4(RFWD3):c.2065dup (p.Thr689fs)	Likely pathogenic

SpliceAI

1999 predictions. Top by Δscore:

Variant	Effect	Δscore
16:74624067:CACAG:C	acceptor_gain	1.0000
16:74624068:ACAG:A	acceptor_gain	1.0000
16:74624069:CAG:C	acceptor_gain	1.0000
16:74624069:CAGC:C	acceptor_gain	1.0000
16:74624070:AGCTA:A	acceptor_loss	1.0000
16:74624071:GCTAA:G	acceptor_loss	1.0000
16:74624072:C:CC	acceptor_gain	1.0000
16:74624072:CTAA:C	acceptor_loss	1.0000
16:74626551:TTAT:T	acceptor_gain	1.0000
16:74626552:TAT:T	acceptor_gain	1.0000
16:74626555:C:CA	acceptor_loss	1.0000
16:74626555:C:CC	acceptor_gain	1.0000
16:74626556:T:G	acceptor_loss	1.0000
16:74628447:CTTA:C	donor_loss	1.0000
16:74628448:TTAC:T	donor_loss	1.0000
16:74628449:TACC:T	donor_loss	1.0000
16:74628450:A:AC	donor_gain	1.0000
16:74628450:ACC:A	donor_loss	1.0000
16:74628451:C:A	donor_loss	1.0000
16:74628451:C:CC	donor_gain	1.0000
16:74628451:CCAGG:C	donor_gain	1.0000
16:74628665:ATC:A	acceptor_loss	1.0000
16:74628666:TC:T	acceptor_loss	1.0000
16:74628667:C:CC	acceptor_gain	1.0000
16:74630775:CCCTA:C	donor_loss	1.0000
16:74630776:CCTA:C	donor_loss	1.0000
16:74630777:CTA:C	donor_loss	1.0000
16:74630778:TAC:T	donor_loss	1.0000
16:74630779:A:AG	donor_loss	1.0000
16:74630780:CCT:C	donor_loss	1.0000

AlphaMissense

5054 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:74630908:A:G	W543R	0.999
16:74630908:A:T	W543R	0.999
16:74644452:C:G	C330S	0.999
16:74644453:A:T	C330S	0.999
16:74644549:A:G	C327R	0.999
16:74644593:C:T	G312E	0.999
16:74644595:A:C	F311L	0.999
16:74644595:A:T	F311L	0.999
16:74644597:A:G	F311L	0.999
16:74644605:C:T	G308E	0.999
16:74644609:A:G	C307R	0.999
16:74644669:A:G	C287R	0.999
16:74630906:C:A	W543C	0.998
16:74630906:C:G	W543C	0.998
16:74630910:A:T	V542D	0.998
16:74644453:A:G	C330R	0.998
16:74644548:C:G	C327S	0.998
16:74644549:A:T	C327S	0.998
16:74644584:C:G	C315S	0.998
16:74644585:A:G	C315R	0.998
16:74644585:A:T	C315S	0.998
16:74644601:A:C	H309Q	0.998
16:74644601:A:T	H309Q	0.998
16:74644605:C:A	G308V	0.998
16:74644608:C:G	C307S	0.998
16:74644609:A:T	C307S	0.998
16:74644648:A:G	W294R	0.998
16:74644648:A:T	W294R	0.998
16:74644660:A:G	C290R	0.998
16:74628469:A:G	L651P	0.997

dbSNP variants (sampled 300 via entrez): RS1000039792 (16:74631918 T>C), RS1000070959 (16:74632067 C>T), RS1000174234 (16:74644520 G>A), RS1000186609 (16:74664366 C>A,G), RS1000214364 (16:74626814 A>G), RS1000281965 (16:74649105 A>T), RS1000298995 (16:74654097 T>C), RS1000379358 (16:74622176 G>A,C), RS1000471029 (16:74666476 G>C), RS1000520917 (16:74663297 C>G,T), RS1000522130 (16:74631254 C>T), RS1000579400 (16:74635275 T>G), RS1000590474 (16:74632171 A>C,G), RS1000609833 (16:74644889 T>C), RS1000697529 (16:74626165 C>T)

Disease associations

OMIM: gene MIM:614151 | disease phenotypes: MIM:617784, MIM:227650

GenCC curated gene-disease

Disease	Classification	Inheritance
Fanconi anemia, complementation group W	Moderate	Autosomal recessive
Fanconi anemia	Supportive	Autosomal recessive
Tourette syndrome	No Known Disease Relationship	Unknown

Mondo (3): Fanconi anemia, complementation group W (MONDO:0044325), Fanconi anemia (MONDO:0019391), Tourette syndrome (MONDO:0007661)

Orphanet (1): Fanconi anemia (Orphanet:84)

HPO phenotypes

119 total (30 of 119 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000035	Abnormal testis morphology
HP:0000047	Hypospadias
HP:0000072	Hydroureter
HP:0000079	Abnormality of the urinary system
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000130	Abnormality of the uterus
HP:0000135	Hypogonadism
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000364	Hearing abnormality
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000453	Choanal atresia
HP:0000478	Abnormality of the eye
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000492	Abnormal eyelid morphology

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002023_2	Testicular germ cell tumor	5.000000e-12
GCST004483_7	Multiple myeloma	5.000000e-12
GCST004635_33	Testicular germ cell tumor	7.000000e-12
GCST004713_33	Testicular germ cell tumor	6.000000e-11
GCST006944_58	Experiencing mood swings	3.000000e-08
GCST009856_20	Leukocyte telomere length	4.000000e-08
GCST010988_49	Adult body size	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008475	mood instability measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
sodium arsenite	increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	affects cotreatment, decreases methylation	1
TAK-243	increases sumoylation	1
bisphenol A	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
CPG-oligonucleotide	decreases expression	1
K 7174	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Dasatinib	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	affects phosphorylation	1
Calcitriol	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Methapyrilene	increases methylation	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2DP	Abcam HeLa RFWD3 KO	Cancer cell line	Female
CVCL_TI89	HAP1 RFWD3 (-) 1	Cancer cell line	Male
CVCL_TI90	HAP1 RFWD3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

267 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT06519786	PHASE3	UNKNOWN	Safety and Efficacy of Metformin for Treatment of Cytopenia in Children and Adolescents With Fanconi Anemia
NCT00004393	PHASE2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	PHASE2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	PHASE2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	PHASE2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	PHASE2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	PHASE2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	PHASE2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	PHASE2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	PHASE2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder
NCT02102698	PHASE2	COMPLETED	Ecopipam Treatment of Tourette’s Syndrome in Subjects 7-17 Years
NCT02217007	PHASE2	WITHDRAWN	A Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of SNC-102 in Subjects With Tourette Syndrome
NCT02247206	PHASE2	COMPLETED	VoIP Delivered Behavior Therapy for Tourette Syndrome
NCT02581865	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome
NCT02619084	PHASE2	COMPLETED	Subthalamic Stimulation in Tourette’s Syndrome
NCT02679079	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Children and Adolescents With Tourette Syndrome
NCT02879578	PHASE2	COMPLETED	Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects With Tourette Syndrome
NCT03066193	PHASE2	COMPLETED	Efficacy of a Therapeutic Combination of Dronabinol and PEA for Tourette Syndrome
NCT03247244	PHASE2	TERMINATED	Safety and Efficacy of Cannabis in Tourette Syndrome
NCT03325010	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome