RNF216

Summary

RNF216 (ring finger protein 216, HGNC:21698) is a protein-coding gene on chromosome 7p22.1, encoding E3 ubiquitin-protein ligase RNF216 (Q9NWF9). E3 ubiquitin ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their ubiquitination.

This gene encodes a cytoplasmic protein which specifically colocalizes and interacts with the serine/threonine protein kinase, receptor-interacting protein (RIP). Zinc finger domains of the encoded protein are required for its interaction with RIP and for inhibition of TNF- and IL1-induced NF-kappa B activation pathways. The encoded protein may also function as an E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes and transfers it to substrates. Several alternatively spliced transcript variants have been described for this locus but the full-length natures of only some are known.

Source: NCBI Gene 54476 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar ataxia-hypogonadism syndrome (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 413 total — 17 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 32
• MANE Select transcript: NM_207111

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21698
Approved symbol	RNF216
Name	ring finger protein 216
Location	7p22.1
Locus type	gene with protein product
Status	Approved
Aliases	TRIAD3, UBCE7IP1, ZIN
Ensembl gene	ENSG00000011275
Ensembl biotype	protein_coding
OMIM	609948
Entrez	54476

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 3 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000389900, ENST00000389902, ENST00000411812, ENST00000416985, ENST00000425013, ENST00000469375, ENST00000476345, ENST00000479541, ENST00000484458

RefSeq mRNA: 3 — MANE Select: NM_207111 NM_001377156, NM_207111, NM_207116

CCDS: CCDS34594, CCDS34595

Canonical transcript exons

ENST00000389902 — 17 exons

Exon	Start	End
ENSE00001363716	5740973	5741815
ENSE00001422787	5761003	5761138
ENSE00001594969	5739276	5739352
ENSE00001707537	5620047	5623179
ENSE00001888901	5781541	5781663
ENSE00003471327	5712715	5712863
ENSE00003522617	5721033	5721172
ENSE00003541993	5711761	5711839
ENSE00003561395	5729432	5729596
ENSE00003579008	5652413	5652510
ENSE00003585990	5641154	5641376
ENSE00003601820	5716716	5716766
ENSE00003630046	5730715	5730817
ENSE00003663399	5752846	5752979
ENSE00003669038	5624056	5624125
ENSE00003681788	5715053	5715190
ENSE00003689978	5725324	5725438

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 92.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.8218 / max 240.6564, expressed in 1817 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82618	34.0187	1816
82619	0.4908	286
82616	0.2889	112
82617	0.0234	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.33	gold quality
right testis	UBERON:0004534	92.20	gold quality
left testis	UBERON:0004533	92.11	gold quality
saphenous vein	UBERON:0007318	91.00	gold quality
testis	UBERON:0000473	90.95	gold quality
sperm	CL:0000019	90.64	gold quality
stromal cell of endometrium	CL:0002255	90.42	gold quality
oocyte	CL:0000023	90.12	gold quality
male germ cell	CL:0000015	89.98	gold quality
granulocyte	CL:0000094	89.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.66	gold quality
calcaneal tendon	UBERON:0003701	89.65	gold quality
lower esophagus	UBERON:0013473	89.62	gold quality
secondary oocyte	CL:0000655	89.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.42	gold quality
mucosa of stomach	UBERON:0001199	89.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.50	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.47	gold quality
adrenal tissue	UBERON:0018303	88.32	gold quality
lymph node	UBERON:0000029	88.14	gold quality
popliteal artery	UBERON:0002250	88.01	gold quality
tibial artery	UBERON:0007610	88.01	gold quality
aorta	UBERON:0000947	87.85	gold quality
blood	UBERON:0000178	87.75	gold quality
ascending aorta	UBERON:0001496	87.72	gold quality
thoracic aorta	UBERON:0001515	87.68	gold quality
smooth muscle tissue	UBERON:0001135	87.42	gold quality
corpus callosum	UBERON:0002336	87.41	gold quality
right atrium auricular region	UBERON:0006631	87.21	gold quality
sural nerve	UBERON:0015488	87.10	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.97
E-CURD-53	no	347.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting RNF216, 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-8485	100.00	77.57	4731
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-145-5P	99.92	71.13	1836

Literature-anchored findings (GeneRIF, showing 21)

• interacts with RIP and inhibits tnf and il1-induced NFKB activation (PMID:11854271)
• ZIN binds to purified Vif in vitro and Triad 3/ZIN interacts with HIV-1 Vif in transfected human 293T cells, as demonstrated by coimmunoprecipitation (PMID:15367624)
• Triad3A regulates ubiquitination and proteasomal degradation of RIP1 following disruption of Hsp90 binding and play a crucial role in innate immunity (PMID:16968706)
• Gene expression of RIPK3 and RNF216 in PBMC could identify those obese subjects, who will regain more weight after a successful initial weight loss. The mRNA levels of these genes could be nutrigenomic biomarkers for predicting obesity treatment outcome. (PMID:19690434)
• Triad3A represents a versatile E3 ubiquitin ligase that negatively regulates RIG-like receptor signaling by targeting TRAF3 for degradation following RNA virus infection. (PMID:19893624)
• By promoting polyubiquitylation and degradation, E3 ubiquitin ligase Triad3A is identified as an interaction partner for the killer cell Ig-like receptor KIR2DL4 cytoplasmic domain. (PMID:21270397)
• The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. (PMID:23656588)
• Loss of Triad3A mimics and occludes Arc-dependent forms of synaptic plasticity. (PMID:24945773)
• Novel RNF216 mutations causing an Huntington-like phenotype with pure monogenic recessive inheritance. . (PMID:25841028)
• RNF216 is a potential biomarker and novel therapeutic target for inhibiting colorectal carcinoma development and progression. (PMID:27203674)
• missense mutations in TRIAD3 abolished the interaction of TRIAD3A with Arc, disrupting Arc ubiquitination, and consequently Arc degradation. (PMID:27995769)
• ICM inhibited autophagy by inhibiting nucleocytoplasmic translocation of HMGB1 and by increasing Beclin 1 ubiquitylation for degradation by enhancing the interaction between Beclin 1 and E3 ubiquitin ligase RNF216 (PMID:29361549)
• An essential function of RNF216 in spermatogenesis and male fertility and suggest a critical role for RNF216 in human gonadal development. (PMID:30649198)
• that TLR8 proteasomal disposal through RNF216 in response to RNA ligands regulates TLR8 cellular concentrations (PMID:31385713)
• RNF216 regulates meiosis and PKA stability in the testes. (PMID:33724554)
• [Screening of interacting proteins of idiopathic gonadotropin-releasing hormone deficiency pathogenic gene RNF216]. (PMID:34247365)
• Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216. (PMID:34998453)
• Whole-Exome Sequencing Identified a Novel Mutation in RNF216 in a Family with Gordon Holmes Syndrome. (PMID:35088240)
• RNF216 affects the stability of STAU2 in the hypothalamus. (PMID:37439148)
• Clinical and genetic spectrum of RNF216-related disorder: a new case and literature review. (PMID:38050071)
• Ring finger protein 216 loss-of-function induces white matter hyperintensities by inhibiting oligodendroglia proliferation. (PMID:38853469)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf216	ENSDARG00000087893
mus_musculus	Rnf216	ENSMUSG00000045078
rattus_norvegicus	Rnf216	ENSRNOG00000001101
caenorhabditis_elegans		WBGENE00013270

Paralogs (2): RBCK1 (ENSG00000125826), SHARPIN (ENSG00000179526)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF216 — Q9NWF9 (reviewed: Q9NWF9)

Alternative names: RING finger protein 216, RING-type E3 ubiquitin transferase RNF216, Triad domain-containing protein 3, Ubiquitin-conjugating enzyme 7-interacting protein 1, Zinc finger protein inhibiting NF-kappa-B

All UniProt accessions (4): Q9NWF9, C9JIV3, F8W6D1, F8WDI8

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their ubiquitination. Plays a role in the regulation of antiviral responses by promoting the degradation of TRAF3, TLR4 and TLR9. In turn, down-regulates NF-kappa-B and IRF3 activation as well as beta interferon production. Also participates in the regulation of autophagy by ubiquitinating BECN1 leading to its degradation and autophagy inhibition. Plays a role in ARC-dependent synaptic plasticity by mediating ARC ubiquitination resulting in its rapid proteasomal degradation. Plays aso an essential role in spermatogenesis and male fertility. Mechanistically, regulates meiosis by promoting the degradation of PRKACB through the ubiquitin-mediated lysosome pathway. Modulates the gonadotropin-releasing hormone signal pathway by affecting the stability of STAU2 that is required for the microtubule-dependent transport of neuronal RNA from the cell body to the dendrite. Inhibits TNF and IL-1 mediated activation of NF-kappa-B. Promotes TNF and RIP mediated apoptosis.

Subunit / interactions. Interacts with UBE2L3 and to some extent with UBE2L6. Interacts with TRAF3, TLR3, TLR4, TLR5 and TLR9. Isoform 3/ZIN binds RIPK1. (Microbial infection) Isoform 3/ZIN binds RIPK1 and HIV Vif.

Subcellular location. Cytoplasm. Cytoplasmic vesicle. Clathrin-coated vesicle.

Tissue specificity. Ubiquitous, with the highest levels of expression in testis and peripheral blood leukocytes.

Post-translational modifications. Auto-ubiquitinated. Phosphorylation at Ser-719 enhances acceptor ubiquitin binding and chain-type specificity towards ‘Lys-63’ di-ubiquitin but not di-ubiquitin with other linkage types.

Disease relevance. Gordon Holmes syndrome (GDHS) [MIM:212840] A disease characterized by cerebellar symptoms and signs of sex steroid deficiency. Clinical features include cerebellar and brain stem atrophy, cerebellar ataxia, hypothalamic LHRH deficiency, hypogonadotrophic hypogonadism, lack of secondary sexual characteristics, and infertility. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosterically activated by ‘Lys-63’-linked di-ubiquitin.

Domain organisation. The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. 4 different alternatively spliced mRNAs code for this protein isoform.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NWF9-2	1, TRIAD3A	yes
Q9NWF9-1	2, TRIAD3B
Q9NWF9-3	3, ZIN, TRIAD3

RefSeq proteins (3): NP_001364085, NP_996994, NP_996999 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002867	IBR_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR044066	TRIAD_supradom	Domain
IPR047544	RING-HC_RBR_RNF216	Domain
IPR047545	BRcat_RBR_RNF216	Domain
IPR047546	Rcat_RBR_RNF216	Domain
IPR051628	LUBAC_E3_Ligases	Family
IPR058758	UBA_RNF216	Domain

Pfam: PF26112, PF26191, PF26200

UniProt features (85 total): binding site 20, cross-link 15, strand 13, helix 8, turn 5, region of interest 4, mutagenesis site 4, zinc finger region 3, compositionally biased region 2, modified residue 2, splice variant 2, sequence variant 2, coiled-coil region 2, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7M4O	X-RAY DIFFRACTION	2.21
7M4M	X-RAY DIFFRACTION	2.39
7M4N	X-RAY DIFFRACTION	2.52
8EB0	X-RAY DIFFRACTION	3.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWF9-F1	62.91	0.14

Functional residue map

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

Catalytic / active sites (1): 688

Ligand- & substrate-binding residues (20): 515; 518; 537; 540; 605; 608; 623; 628; 633; 636; 643; 648 …

Post-translational modifications (17): 419, 719, 100, 351, 354, 425, 430, 448, 459, 485, 619, 658, 666, 765, 773, 80, 89

Mutagenesis-validated functional residues (4):

Position	Phenotype
664	abrogates ubiquitin chain formation activity.
672	abrogates ubiquitin chain formation activity.
683	abrogates ubiquitin chain formation activity.
719	mild reduced activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta

MSigDB gene sets: 260 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, CAGCTG_AP4_Q5, chr7p22, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, WCTCNATGGY_UNKNOWN, GOCC_COATED_VESICLE, GOBP_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION

GO Biological Process (7): apoptotic process (GO:0006915), negative regulation of type I interferon production (GO:0032480), regulation of interferon-beta production (GO:0032648), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of defense response to virus by host (GO:0050691), protein K48-linked ubiquitination (GO:0070936), protein ubiquitination (GO:0016567)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), clathrin-coated vesicle (GO:0030136), cytoplasm (GO:0005737), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
Immune System	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of type I interferon production	2
cytoplasm	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
negative regulation of cytokine production	1
type I interferon production	1
interferon-beta production	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
regulation of defense response to virus	1
protein polyubiquitination	1
protein modification by small protein conjugation	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
coated vesicle	1
intracellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

1116 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF216	RIPK1	Q13546	767
RNF216	OTUD4	Q01804	692
RNF216	RNF14	Q9UBS8	603
RNF216	PNPLA6	Q8IY17	585
RNF216	TIRAP	P58753	531
RNF216	ANKIB1	Q9P2G1	492
RNF216	TICAM1	Q8IUC6	487
RNF216	PPHLN1	Q8NEY8	487
RNF216	POLR3A	O14802	477
RNF216	KLHL20	Q9Y2M5	471
RNF216	SMURF1	Q9HCE7	461
RNF216	PIP4K2C	Q8TBX8	451
RNF216	ARHGAP15	Q53QZ3	447
RNF216	STUB1	Q9UNE7	446
RNF216	TLR4	O00206	444

IntAct

57 interactions, top by confidence:

A	B	Type	Score
MTURN	RNF216	psi-mi:“MI:0915”(physical association)	0.560
KHNYN	RNF216	psi-mi:“MI:0915”(physical association)	0.560
RNF216	MTURN	psi-mi:“MI:0915”(physical association)	0.560
YOD1	RNF216	psi-mi:“MI:0915”(physical association)	0.560
MORC3	RNF216	psi-mi:“MI:0915”(physical association)	0.560
UBASH3B	RNF216	psi-mi:“MI:0915”(physical association)	0.560
UBAC1	RNF216	psi-mi:“MI:0915”(physical association)	0.560
CAPN15	RNF216	psi-mi:“MI:0915”(physical association)	0.560
USP5	RNF216	psi-mi:“MI:0915”(physical association)	0.560
OPTN	RNF216	psi-mi:“MI:0915”(physical association)	0.560
TNFAIP3	RNF216	psi-mi:“MI:0915”(physical association)	0.560
UBE2L3	RNF216	psi-mi:“MI:0915”(physical association)	0.560
ZFAND2A	RNF216	psi-mi:“MI:0915”(physical association)	0.560
UBE2L6	RNF216	psi-mi:“MI:0915”(physical association)	0.560
FAM168A	RNF216	psi-mi:“MI:0915”(physical association)	0.560
UBASH3A	RNF216	psi-mi:“MI:0915”(physical association)	0.560
PLEKHN1	RNF216	psi-mi:“MI:0915”(physical association)	0.400
RNF216	ENTREP1	psi-mi:“MI:0915”(physical association)	0.370
UBAC1	RNF216	psi-mi:“MI:0915”(physical association)	0.370
RNF216	RNF11	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
RNF216	RRAD	psi-mi:“MI:0914”(association)	0.350
URGCP	TOM1	psi-mi:“MI:0914”(association)	0.350
UBASH3B	RNF216	psi-mi:“MI:0915”(physical association)	0.000
UBAC1	RNF216	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (95): RNF216 (Affinity Capture-RNA), RNF216 (Affinity Capture-RNA), RNF216 (Affinity Capture-MS), BECN1 (Affinity Capture-Western), RNF216 (Affinity Capture-Western), RNF216 (Affinity Capture-Western), ARC (Affinity Capture-Western), ARC (Affinity Capture-Western), RIPK1 (Affinity Capture-Western), RNF216 (Affinity Capture-Western), TRAF3 (Biochemical Activity), UBE2D3 (Reconstituted Complex), RNF216 (Affinity Capture-RNA), RNF216 (Affinity Capture-MS), RNF216 (Reconstituted Complex)

ESM2 similar proteins: A2RRT3, A8WWR3, A8X0L9, B3M1F2, B3P4M4, B4GZ07, B4HJA7, B4JSL2, B4KCG1, B4M686, B4N8G7, B4PVI7, B4QVV3, H2L056, O13731, O60106, O74757, O94400, O94527, P03182, P0C6Z1, P0C736, P13810, P23801, P29469, P32828, P34256, P34470, P41957, P41958, P43528, P58283, P90859, Q09268, Q0D2D2, Q29B72, Q626N3, Q75CC8, Q8GWG6, Q8GYT9

Diamond homologs: P58283, Q6NUR6, Q9NWF9

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF216	ubiquitination
RNF216	“down-regulates quantity by destabilization”	TLR4	ubiquitination
RNF216	“down-regulates quantity by destabilization”	TLR9	ubiquitination
RNF216	“down-regulates quantity by destabilization”	TIRAP	ubiquitination
RNF216	“down-regulates quantity by destabilization”	RIPK1	ubiquitination
RNF216	“down-regulates quantity by destabilization”	TICAM1	ubiquitination
RNF216	“down-regulates quantity by destabilization”	TLR8	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	8
Uncertain significance	219
Likely benign	131
Benign	13

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1343797	NM_207111.4(RNF216):c.2149C>T (p.Arg717Cys)	Pathogenic
1395629	NM_207111.4(RNF216):c.1681G>T (p.Glu561Ter)	Pathogenic
1804037	NM_207111.4(RNF216):c.991C>T (p.Gln331Ter)	Pathogenic
199654	NM_207111.4(RNF216):c.1367G>A (p.Gly456Glu)	Pathogenic
199655	NM_207111.4(RNF216):c.904C>T (p.Gln302Ter)	Pathogenic
2129722	NM_207111.4(RNF216):c.1583_1584del (p.Leu528fs)	Pathogenic
2444427	NM_207111.4(RNF216):c.986G>A (p.Trp329Ter)	Pathogenic
2721883	NM_207111.4(RNF216):c.1549C>T (p.Arg517Ter)	Pathogenic
3720727	NM_207111.4(RNF216):c.2056C>T (p.Arg686Ter)	Pathogenic
4532074	NM_207111.4(RNF216):c.1731_1732del (p.Glu578fs)	Pathogenic
4734858	NM_207111.4(RNF216):c.1606C>T (p.Gln536Ter)	Pathogenic
50912	NM_207111.4(RNF216):c.2251C>T (p.Arg751Cys)	Pathogenic
50913	NM_207111.4(RNF216):c.1791T>A (p.Cys597Ter)	Pathogenic
50914	NM_207111.4(RNF216):c.615_616del (p.Glu205fs)	Pathogenic
587594	NM_207111.4(RNF216):c.202-1G>C	Pathogenic
813323	GRCh37/hg19 7p22.1(chr7:5692044-5692141)	Pathogenic
817880	NM_207111.4(RNF216):c.930del (p.Glu310fs)	Pathogenic
1027514	NM_207111.4(RNF216):c.2061+3A>G	Likely pathogenic
1027515	NM_207111.4(RNF216):c.1849A>G (p.Met617Val)	Likely pathogenic
1348614	NC_000007.13:g.(?5792457)(5792630_?)dup	Likely pathogenic
183356	NM_207111.4(RNF216):c.2061G>A (p.Lys687=)	Likely pathogenic
2682870	NM_207111.4(RNF216):c.345_351del (p.Asn116fs)	Likely pathogenic
3245944	NC_000007.13:g.(?5756327)(5792630_?)dup	Likely pathogenic
3602193	NM_207111.4(RNF216):c.1754C>T (p.Thr585Met)	Likely pathogenic
563347	GRCh37/hg19 7p22.1(chr7:5606650-5974130)x3	Likely pathogenic

SpliceAI

4227 predictions. Top by Δscore:

Variant	Effect	Δscore
7:5641146:CTACT:C	donor_loss	1.0000
7:5641147:TACTT:T	donor_loss	1.0000
7:5641148:ACTTA:A	donor_loss	1.0000
7:5641149:CTTAC:C	donor_loss	1.0000
7:5641150:TTACA:T	donor_loss	1.0000
7:5641151:TA:T	donor_loss	1.0000
7:5641152:A:AC	donor_gain	1.0000
7:5641152:A:AT	donor_loss	1.0000
7:5641153:C:CT	donor_gain	1.0000
7:5641153:CA:C	donor_gain	1.0000
7:5641153:CAG:C	donor_gain	1.0000
7:5641153:CAGT:C	donor_gain	1.0000
7:5641153:CAGTG:C	donor_gain	1.0000
7:5641375:CA:C	acceptor_gain	1.0000
7:5641377:C:CC	acceptor_gain	1.0000
7:5652411:A:AC	donor_gain	1.0000
7:5652412:C:CG	donor_gain	1.0000
7:5652412:CAT:C	donor_gain	1.0000
7:5652412:CATAG:C	donor_gain	1.0000
7:5688983:C:CA	donor_gain	1.0000
7:5712710:CGAA:C	donor_loss	1.0000
7:5712711:GAA:G	donor_loss	1.0000
7:5712712:AACCT:A	donor_loss	1.0000
7:5712714:CCTG:C	donor_loss	1.0000
7:5712859:TCCAA:T	acceptor_gain	1.0000
7:5712860:CCAA:C	acceptor_gain	1.0000
7:5712860:CCAAC:C	acceptor_gain	1.0000
7:5712861:CAA:C	acceptor_gain	1.0000
7:5712861:CAAC:C	acceptor_gain	1.0000
7:5712862:AA:A	acceptor_gain	1.0000

AlphaMissense

6152 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:5641166:C:A	W733C	1.000
7:5641166:C:G	W733C	1.000
7:5641168:A:G	W733R	1.000
7:5641168:A:T	W733R	1.000
7:5641176:C:G	C730S	1.000
7:5641177:A:G	C730R	1.000
7:5641177:A:T	C730S	1.000
7:5641195:A:G	C724R	1.000
7:5641225:A:G	C714R	1.000
7:5641226:G:C	F713L	1.000
7:5641226:G:T	F713L	1.000
7:5641227:A:C	F713C	1.000
7:5641227:A:G	F713S	1.000
7:5641228:A:G	F713L	1.000
7:5641267:A:G	C700R	1.000
7:5641288:A:G	C693R	1.000
7:5641298:G:C	N689K	1.000
7:5641298:G:T	N689K	1.000
7:5641303:A:G	C688R	1.000
7:5641306:C:A	G687C	1.000
7:5641306:C:G	G687R	1.000
7:5641313:T:A	K684N	1.000
7:5641313:T:G	K684N	1.000
7:5641315:T:C	K684E	1.000
7:5641341:C:G	C675S	1.000
7:5641342:A:G	C675R	1.000
7:5641342:A:T	C675S	1.000
7:5641346:T:A	R673S	1.000
7:5641346:T:G	R673S	1.000
7:5641347:C:G	R673T	1.000

dbSNP variants (sampled 300 via entrez): RS1000002970 (7:5778441 C>A,G), RS1000008517 (7:5655443 C>A), RS1000011619 (7:5701823 G>A), RS1000015638 (7:5635489 C>T), RS1000054029 (7:5665680 G>A,C), RS1000102660 (7:5689894 T>A,C), RS1000108940 (7:5621121 T>C), RS1000123181 (7:5779006 A>G), RS1000127220 (7:5714564 T>A,C,G), RS1000158022 (7:5666027 G>A,T), RS1000159605 (7:5780714 G>A,C), RS1000191094 (7:5727240 C>A), RS1000196310 (7:5670693 T>A), RS1000205994 (7:5677598 T>C), RS1000213024 (7:5750089 T>A,C)

Disease associations

OMIM: gene MIM:609948 | disease phenotypes: MIM:212840, MIM:146110, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar ataxia-hypogonadism syndrome	Strong	Autosomal recessive

Mondo (4): cerebellar ataxia-hypogonadism syndrome (MONDO:0008935), hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), leukodystrophy (MONDO:0019046), rosette-forming glioneuronal tumor of fourth ventricule (MONDO:0016736)

Orphanet (4): Cerebellar ataxia-hypogonadism syndrome (Orphanet:1173), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Leukodystrophy (Orphanet:68356), Rosette-forming glioneuronal tumor (Orphanet:251975)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000044	Hypogonadotropic hypogonadism
HP:0000135	Hypogonadism
HP:0000144	Decreased fertility
HP:0000248	Brachycephaly
HP:0000512	Abnormal electroretinogram
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000726	Dementia
HP:0000751	Personality changes
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000869	Secondary amenorrhea
HP:0000876	Oligomenorrhea
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0002059	Cerebral atrophy
HP:0002072	Chorea
HP:0002167	Abnormal speech pattern
HP:0002558	Supernumerary nipple
HP:0003621	Juvenile onset
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0004374	Hemiplegia/hemiparesis
HP:0007703	Abnormal retinal pigmentation
HP:0008197	Absence of pubertal development

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST012489_70	Heel bone mineral density x serum urate levels interaction	3.000000e-09
GCST90000015_12	Parkinson’s disease motor subtype (tremor to postural instability/gait difficulty score ratio)	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0600011	Parkinson’s disease symptom measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C565870	Cerebellar Ataxia and Hypogonadotropic Hypogonadism (supp.)
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, affects methylation	2
GSK-J4	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
testosterone undecanoate	increases expression, affects cotreatment	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
zinc chromate	decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
pinostrobin	increases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
PCI 5002	increases expression, affects cotreatment	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Zinc	increases expression, affects cotreatment	1
Levonorgestrel	affects cotreatment, increases expression	1

Cellosaurus cell lines

5 cell lines: 4 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6I1	FDHSi003-A	Induced pluripotent stem cell	Male
CVCL_E4UV	KOLF2.1J RNF216 70.9kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E4UX	KOLF2.1J RNF216 R694C SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E4UY	KOLF2.1J RNF216 R694C SNV/WT	Induced pluripotent stem cell	Male
CVCL_TJ35	HAP1 RNF216 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease