RNF135

Summary

RNF135 (ring finger protein 135, HGNC:21158) is a protein-coding gene on chromosome 17q11.2, encoding E3 ubiquitin-protein ligase RNF135 (Q8IUD6). E2-dependent E3 ubiquitin-protein ligase that functions as a RIGI coreceptor in the sensing of viral RNAs in cell cytoplasm and the activation of the antiviral innate immune response.

The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. This gene is located in a chromosomal region known to be frequently deleted in patients with neurofibromatosis. Alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 84282 — RefSeq curated summary.

At a glance

• Gene–disease (curated): overgrowth-macrocephaly-facial dysmorphism syndrome (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 141 total — 2 pathogenic
• Phenotypes (HPO): 26
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_032322

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21158
Approved symbol	RNF135
Name	ring finger protein 135
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC13061
Ensembl gene	ENSG00000181481
Ensembl biotype	protein_coding
OMIM	611358
Entrez	84282

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 12 protein_coding

ENST00000324689, ENST00000328381, ENST00000434242, ENST00000443677, ENST00000535306, ENST00000580444, ENST00000857517, ENST00000857518, ENST00000951324, ENST00000951325, ENST00000951326, ENST00000951327

RefSeq mRNA: 3 — MANE Select: NM_032322 NM_001184992, NM_032322, NM_197939

CCDS: CCDS11262, CCDS11263, CCDS54104

Canonical transcript exons

ENST00000328381 — 5 exons

Exon	Start	End
ENSE00002223347	30971039	30971445
ENSE00002336857	30987944	30988106
ENSE00002418700	30984617	30984760
ENSE00003477855	30997242	30997331
ENSE00003664235	30998662	30999911

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 97.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4526 / max 108.7526, expressed in 1712 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160173	12.4526	1712

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	97.53	gold quality
parietal pleura	UBERON:0002400	96.84	gold quality
layer of synovial tissue	UBERON:0007616	96.74	gold quality
visceral pleura	UBERON:0002401	96.69	gold quality
upper arm skin	UBERON:0004263	96.66	gold quality
ileal mucosa	UBERON:0000331	96.43	gold quality
secondary oocyte	CL:0000655	96.19	gold quality
gingival epithelium	UBERON:0001949	95.69	gold quality
kidney epithelium	UBERON:0004819	95.55	gold quality
esophagus squamous epithelium	UBERON:0006920	95.50	gold quality
penis	UBERON:0000989	95.37	gold quality
oocyte	CL:0000023	95.29	gold quality
gingiva	UBERON:0001828	95.28	gold quality
synovial joint	UBERON:0002217	95.26	gold quality
epithelial cell of pancreas	CL:0000083	95.15	gold quality
nipple	UBERON:0002030	94.94	gold quality
amniotic fluid	UBERON:0000173	94.69	gold quality
skin of hip	UBERON:0001554	94.40	gold quality
upper leg skin	UBERON:0004262	94.04	gold quality
monocyte	CL:0000576	93.85	gold quality
leukocyte	CL:0000738	93.65	gold quality
decidua	UBERON:0002450	93.61	gold quality
epithelium of nasopharynx	UBERON:0001951	93.56	gold quality
tibia	UBERON:0000979	93.26	gold quality
epithelium of mammary gland	UBERON:0003244	93.20	gold quality
mammary duct	UBERON:0001765	93.17	gold quality
germinal epithelium of ovary	UBERON:0001304	93.04	gold quality
urethra	UBERON:0000057	92.90	gold quality
mammary gland	UBERON:0001911	92.75	gold quality
thoracic mammary gland	UBERON:0005200	92.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.91
E-GEOD-99795	no	106.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting RNF135, 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-150-5P	99.99	66.69	1976
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-10399-5P	99.17	69.87	2610

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 16)

• These data identify RNF135 as causative of a new overgrowth syndrome and demonstrate that RNF135 haploinsufficiency contributes to the phenotype of NF1 microdeletion cases. (PMID:17632510)
• identify an alternative factor, Riplet/RNF135, that promotes RIG-I activation independent of TRIM25 (PMID:19017631)
• RNF135 mutations are not present in patients with Sotos syndrome-like features. (PMID:19291764)
• REUL is an E3 ubiquitin ligase of RIG-I and specifically stimulates RIG-I-mediated innate antiviral activity (PMID:19484123)
• Riplet-mediated K63-linked polyubiquitination released RIG-I RD autorepression, which allowed the access of positive factors to the RIG-I protein. (PMID:23950712)
• Data showed that the presence of the RNF135 K115 variant in the genotype of patients with autism was statistically significant. (PMID:26368817)
• findings demonstrate the biological effects of RNF135 in glioblastoma cell proliferation, migration and cell cycle, and its role in the progression of glioblastoma may be associated with the ERK signal transduction pathway. (PMID:26856755)
• In-depth analysis of population-differentiated regions indicated that the coding gene, RNF135, represented a trans-regulation hotspot via cis-regulation by the population-specific variants in the region of selective sweep. (PMID:27992444)
• Together with Riplet, Ube2D3 promotes covalent conjugation of polyubiquitin chains to RIG-I, while Ube2N preferentially facilitates production of unanchored chains. In the presence of these chains, RIG-I induces MAVS aggregation directly on the mitochondria. Data thus reveal two essential mechanisms underlying the activation of RIG-I and MAVS for triggering innate immune signaling in response to viral infection in cells. (PMID:28469175)
• Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity. (PMID:31006531)
• Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG-I. (PMID:31335993)
• A pan-cancer analysis of ring finger protein 135 and its relationship to triple-negative breast cancer proliferation and metastasis. (PMID:36495591)
• The E3 ubiquitin ligase RNF135 modulates chemotherapy resistance to oxaliplatin for colorectal cancer by modulating autophagy. (PMID:38056362)
• Plasma methylated GNB4 and Riplet as a novel dual-marker panel for the detection of hepatocellular carcinoma. (PMID:38154055)
• RNF135 promotes cell proliferation and autophagy in lung adenocarcinoma by promoting the phosphorylation of ULK1. (PMID:38459884)
• RNF135 Promotes Human Osteosarcoma Cell Growth and Inhibits Apoptosis by Upregulating the PI3K/AKT Pathway. (PMID:39118262)

Cross-species orthologs

0 orthologs

Paralogs (12): CD86 (ENSG00000114013), CD274 (ENSG00000120217), CD80 (ENSG00000121594), RFPL1 (ENSG00000128250), RFPL2 (ENSG00000128253), RFPL3 (ENSG00000128276), SPRYD4 (ENSG00000176422), RNF152 (ENSG00000176641), PDCD1LG2 (ENSG00000197646), RFPL4A (ENSG00000223638), RFPL4AL1 (ENSG00000229292), RFPL4B (ENSG00000251258)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF135 — Q8IUD6 (reviewed: Q8IUD6)

Alternative names: RIG-I E3 ubiquitin ligase, RING finger protein 135, RING finger protein leading to RIG-I activation, RING-type E3 ubiquitin transferase RNF135

All UniProt accessions (4): Q8IUD6, H7C3H8, J3QS68, K7EQF1

UniProt curated annotations — full annotation on UniProt →

Function. E2-dependent E3 ubiquitin-protein ligase that functions as a RIGI coreceptor in the sensing of viral RNAs in cell cytoplasm and the activation of the antiviral innate immune response. Together with the UBE2D3, UBE2N and UB2V1 E2 ligases, catalyzes the ‘Lys-63’-linked polyubiquitination of RIGI oligomerized on viral RNAs, an essential step in the activation of the RIG-I signaling pathway. Through a ubiquitin-independent parallel mechanism, which consists in bridging RIGI filaments forming on longer viral RNAs, further activates the RIG-I signaling pathway. This second mechanism that synergizes with the ubiquitin-dependent one would thereby allow an RNA length-dependent regulation of the RIG-I signaling pathway. Associated with the E2 ligase UBE2N, also constitutively synthesizes unanchored ‘Lys-63’-linked polyubiquitin chains that may also activate the RIG-I signaling pathway.

Subunit / interactions. Homodimer. Interacts (homodimer) with RIGI (double-stranded RNA-bound oligomeric form); involved in both RIGI ubiquitination, oligomerization into filaments associated with viral RNAs and the bridging of these filaments. Interacts with UBE2D3 and UBE2N; E2 ubiquitin ligases involved in RNF135-mediated ubiquitination of RIGI and activation of the RIG-I signaling pathway. Interacts with PCBP2.

Subcellular location. Cytoplasm. Stress granule.

Tissue specificity. Expressed in skeletal muscle, spleen, kidney, placenta, prostate, stomach, thyroid and tongue. Also weakly expressed in heart, thymus, liver and lung.

Post-translational modifications. (Microbial infection) Cleaved and inactivated by hepatitis C virus NS3/NS4A.

Domain organisation. The B30.2/SPRY domain mediates the interaction with the substrate RIGI. The coiled-coil domains mediate homodimerization and the bridging of viral RNA-associated RIGI filaments.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IUD6-1	1	yes
Q8IUD6-2	2
Q8IUD6-3	3

RefSeq proteins (3): NP_001171921, NP_115698, NP_922921 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR001870	B30.2/SPRY	Domain
IPR003877	SPRY_dom	Domain
IPR003879	Butyrophylin_SPRY	Domain
IPR006574	PRY	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR042723	RNF135_SPRY_PRY_dom	Domain
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR051051	E3_ubiq-ligase_TRIM/RNF	Family

Pfam: PF00622, PF15227

UniProt features (36 total): strand 14, sequence variant 5, splice variant 4, mutagenesis site 3, sequence conflict 2, coiled-coil region 2, chain 1, domain 1, zinc finger region 1, region of interest 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8G7T	ELECTRON MICROSCOPY	3.2
7JL1	ELECTRON MICROSCOPY	3.9
8G7V	ELECTRON MICROSCOPY	3.9
8G7U	ELECTRON MICROSCOPY	4
7JL3	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUD6-F1	77.15	0.46

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
16–18	prevents degradation by hepatitis c virus ns3/ns4a.
21	loss of function in rig-i signaling pathway; when associated with a-24.
24	loss of function in rig-i signaling pathway; when associated with a-21.

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-918233	TRAF3-dependent IRF activation pathway
R-HSA-933541	TRAF6 mediated IRF7 activation
R-HSA-933542	TRAF6 mediated NF-kB activation
R-HSA-933543	NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-5663205	Infectious disease
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9705683	SARS-CoV-2-host interactions
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 268 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, chr17q11, GTGCCTT_MIR506, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_POSITIVE_REGULATION_OF_INTERFERON_BETA_PRODUCTION, GOBP_CYTOKINE_PRODUCTION, MODULE_206, GOBP_REGULATION_OF_RESPONSE_TO_STRESS

GO Biological Process (11): protein polyubiquitination (GO:0000209), free ubiquitin chain polymerization (GO:0010994), protein ubiquitination (GO:0016567), positive regulation of interferon-beta production (GO:0032728), RIG-I signaling pathway (GO:0039529), innate immune response (GO:0045087), regulation of innate immune response (GO:0045088), protein homooligomerization (GO:0051260), protein K63-linked ubiquitination (GO:0070534), antiviral innate immune response (GO:0140374), immune system process (GO:0002376)

GO Molecular Function (9): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), RIG-I binding (GO:0039552), identical protein binding (GO:0042802), ribonucleoprotein complex binding (GO:0043021), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
DDX58/IFIH1-mediated induction of interferon-alpha/beta	5
Innate Immune System	1
Deubiquitination	1
SARS-CoV-2-host interactions	1
Immune System	1
Disease	1
Post-translational protein modification	1
Metabolism of proteins	1
Viral Infection Pathways	1
SARS-CoV Infections	1
SARS-CoV-2 Infection	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
innate immune response	2
cellular anatomical structure	2
protein ubiquitination	1
ubiquitin recycling	1
protein polymerization	1
protein modification by small protein conjugation	1
positive regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
cytoplasmic pattern recognition receptor signaling pathway	1
immune response	1
defense response to symbiont	1
regulation of response to biotic stimulus	1
regulation of defense response	1
regulation of response to external stimulus	1
regulation of immune response	1
protein complex oligomerization	1
protein polyubiquitination	1
defense response to virus	1
biological_process	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
signaling receptor binding	1
protein binding	1
protein-containing complex binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
cytoplasmic ribonucleoprotein granule	1
protein-containing complex	1

Protein interactions and networks

STRING

964 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF135	RIGI	O95786	871
RNF135	EVI2A	P22794	809
RNF135	EVI2B	P34910	808
RNF135	ADAP2	Q9NPF8	779
RNF135	IFIH1	Q9BYX4	768
RNF135	FHDC1	Q9C0D6	763
RNF135	SSH2	Q76I76	760
RNF135	RNF125	Q96EQ8	714
RNF135	MEX3C	Q5U5Q3	699
RNF135	MAVS	Q7Z434	697
RNF135	NF1	P21359	681
RNF135	DHX58	Q96C10	623
RNF135	SUZ12	Q15022	615
RNF135	IRF3	Q14653	602
RNF135	TEFM	Q96QE5	595

IntAct

38 interactions, top by confidence:

A	B	Type	Score
CTNNAL1	RNF135	psi-mi:“MI:0915”(physical association)	0.780
RNF135	CTNNAL1	psi-mi:“MI:0915”(physical association)	0.780
RNF135	GOLGA2	psi-mi:“MI:0915”(physical association)	0.720
GOLGA2	RNF135	psi-mi:“MI:0915”(physical association)	0.720
RNF135	RNF135	psi-mi:“MI:0915”(physical association)	0.670
HSF2BP	RNF135	psi-mi:“MI:0915”(physical association)	0.670
RNF135	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
CTBP2	RNF135	psi-mi:“MI:0915”(physical association)	0.560
	RNF135	psi-mi:“MI:0915”(physical association)	0.560
RNF135	TXLNA	psi-mi:“MI:0914”(association)	0.530
RNF135	XRCC4	psi-mi:“MI:0914”(association)	0.530
TACC3	DHRS2	psi-mi:“MI:0914”(association)	0.350
BSPRY	DEAF1	psi-mi:“MI:0914”(association)	0.350
HSF2BP	PRC1	psi-mi:“MI:0914”(association)	0.350
BSPRY	SRGAP2	psi-mi:“MI:0914”(association)	0.350
KRT7	NEFL	psi-mi:“MI:0914”(association)	0.350
TXLNA	CENPF	psi-mi:“MI:0914”(association)	0.350
RNF135	HSF2BP	psi-mi:“MI:0915”(physical association)	0.000
RNF135	CTBP2	psi-mi:“MI:0915”(physical association)	0.000
	RNF135	psi-mi:“MI:0915”(physical association)	0.000
RNF135	RNF135	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (81): RNF135 (Two-hybrid), RNF135 (Two-hybrid), RNF135 (Two-hybrid), DDX58 (Biochemical Activity), RNF135 (Affinity Capture-Western), DDX58 (Affinity Capture-Western), RNF135 (Two-hybrid), RNF135 (Affinity Capture-MS), RNF135 (Affinity Capture-MS), CTNNAL1 (Affinity Capture-MS), IQCB1 (Affinity Capture-MS), GTF2H2 (Affinity Capture-MS), XRCC4 (Affinity Capture-MS), TXLNA (Affinity Capture-MS), TES (Affinity Capture-MS)

ESM2 similar proteins: A0JPQ4, E1BD59, O15197, P0C0K6, P62603, Q14142, Q1XH17, Q1XH18, Q3UWZ0, Q5BK82, Q5JZY3, Q5M929, Q5NCC3, Q5RBG2, Q5RKG6, Q5TM55, Q5W0U4, Q640S6, Q6P6S3, Q6PGR9, Q6PJ69, Q6ZMU5, Q7TPM3, Q7YR32, Q80VI1, Q80X56, Q80YW5, Q810I1, Q810I2, Q865W2, Q86UV6, Q86UV7, Q86XT4, Q8BFW4, Q8BVW3, Q8BYG9, Q8C006, Q8C0E3, Q8IUD6, Q8K243

Diamond homologs: E1BD59, E7ERA6, F6ZQ54, O60858, Q03601, Q0IIM1, Q32L60, Q3UIW8, Q503I2, Q5M7V1, Q5ZMD4, Q61510, Q7T308, Q80VI1, Q810I1, Q810I2, Q8BFW4, Q8IUD6, Q9BRZ2, Q9CYB0, A0JN74, A6NLU0, B1H278, D4ABM4, F8VTS6, K7N6K2, O00478, O00481, O00635, O15553, O75677, O75678, O77666, P14373, P15533, P18892, P19474, Q0PF16, Q13410, Q1ACD5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
RNF135	“up-regulates activity”	DDX58	ubiquitination
Ub:E2	“up-regulates activity”	RNF135	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	87
Likely benign	25
Benign	12

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
395436	GRCh37/hg19 17q11.2(chr17:29325832-29326647)x1	Pathogenic
977	NM_032322.4(RNF135):c.1015del (p.Val339fs)	Pathogenic

SpliceAI

1120 predictions. Top by Δscore:

Variant	Effect	Δscore
17:30987955:T:TA	acceptor_gain	1.0000
17:30988105:GG:G	donor_gain	1.0000
17:30988106:GG:G	donor_gain	1.0000
17:30997330:GT:G	donor_gain	1.0000
17:30998658:AAAG:A	acceptor_gain	1.0000
17:30998658:AAAGG:A	acceptor_gain	1.0000
17:30971347:A:G	donor_gain	0.9900
17:30971442:GCGG:G	donor_gain	0.9900
17:30984613:GAAG:G	acceptor_loss	0.9900
17:30984614:AAGGT:A	acceptor_loss	0.9900
17:30984615:A:G	acceptor_loss	0.9900
17:30984616:G:C	acceptor_loss	0.9900
17:30984757:CAAG:C	donor_loss	0.9900
17:30984758:AAG:A	donor_loss	0.9900
17:30984759:AGGT:A	donor_loss	0.9900
17:30984761:G:T	donor_loss	0.9900
17:30984762:T:A	donor_loss	0.9900
17:30987956:G:A	acceptor_gain	0.9900
17:30987960:T:TA	acceptor_gain	0.9900
17:30987961:G:A	acceptor_gain	0.9900
17:30987971:AT:A	acceptor_gain	0.9900
17:30987972:T:G	acceptor_gain	0.9900
17:30987972:T:TA	acceptor_gain	0.9900
17:30987973:G:A	acceptor_gain	0.9900
17:30988102:GCAGG:G	donor_gain	0.9900
17:30988106:GGT:G	donor_loss	0.9900
17:30988108:T:A	donor_loss	0.9900
17:30997238:TTAG:T	acceptor_loss	0.9900
17:30997240:A:C	acceptor_loss	0.9900
17:30997310:A:T	donor_gain	0.9900

AlphaMissense

2797 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:30971191:T:C	F40L	0.995
17:30971193:C:A	F40L	0.995
17:30971193:C:G	F40L	0.995
17:30998781:T:C	F297L	0.992
17:30998783:T:A	F297L	0.992
17:30998783:T:G	F297L	0.992
17:30998835:T:A	W315R	0.988
17:30998835:T:C	W315R	0.988
17:30971188:A:C	S39R	0.987
17:30971190:C:A	S39R	0.987
17:30971190:C:G	S39R	0.987
17:30998865:T:A	W325R	0.987
17:30998865:T:C	W325R	0.987
17:30998868:G:C	A326P	0.985
17:30971134:T:C	C21R	0.981
17:30971187:C:A	H38Q	0.981
17:30971187:C:G	H38Q	0.981
17:30998837:G:C	W315C	0.980
17:30998837:G:T	W315C	0.980
17:30998872:T:A	V327D	0.980
17:30998874:G:T	G328W	0.980
17:30999057:T:C	F389L	0.980
17:30999059:C:A	F389L	0.980
17:30999059:C:G	F389L	0.980
17:30999166:T:C	L425P	0.979
17:30971298:C:A	N75K	0.978
17:30971298:C:G	N75K	0.978
17:30998782:T:C	F297S	0.978
17:30971165:C:A	P31H	0.977
17:30971192:T:C	F40S	0.977

dbSNP variants (sampled 300 via entrez): RS1000013478 (17:30976369 T>C), RS1000177688 (17:30969238 T>C), RS1000183426 (17:30993898 G>A), RS1000417513 (17:30963348 TGAG>T), RS1000454562 (17:30980771 C>G,T), RS1000489252 (17:30986623 G>A), RS1000623668 (17:30999464 G>C), RS1000698140 (17:30969600 T>A), RS1000700390 (17:30992053 T>C), RS1000707214 (17:30967479 T>C), RS1000845710 (17:30972251 C>G), RS1000902433 (17:30978369 G>A), RS1000923030 (17:30961497 C>T), RS1000983845 (17:30966679 G>A,T), RS1001016680 (17:30978121 G>C)

Disease associations

OMIM: gene MIM:611358 | disease phenotypes: MIM:613675

GenCC curated gene-disease

Disease	Classification	Inheritance
overgrowth-macrocephaly-facial dysmorphism syndrome	Supportive	Autosomal dominant
overgrowth syndrome	Limited	Autosomal dominant

Mondo (4): chromosome 17q11.2 deletion syndrome, 1.4Mb (MONDO:0013357), autism spectrum disorder (MONDO:0005258), overgrowth syndrome (MONDO:0019716), (MONDO:0013617)

Orphanet (5): 17q11.2 microduplication syndrome (Orphanet:139474), Neurofibromatosis type 1 (Orphanet:636), 17q11 microdeletion syndrome (Orphanet:97685), Overgrowth-macrocephaly-facial dysmorphism syndrome (Orphanet:137634), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000098	Tall stature
HP:0000179	Thick lower lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000256	Macrocephaly
HP:0000267	Cranial asymmetry
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000365	Hearing impairment
HP:0000455	Broad nasal tip
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000609	Optic nerve hypoplasia
HP:0000729	Autistic behavior
HP:0000766	Abnormal sternum morphology
HP:0000768	Pectus carinatum
HP:0001256	Mild intellectual disability
HP:0001520	Large for gestational age
HP:0001548	Overgrowth
HP:0001641	Abnormal pulmonary valve morphology
HP:0001642	Pulmonic stenosis
HP:0001999	Abnormal facial shape
HP:0005616	Accelerated skeletal maturation
HP:0008058	Aplasia/Hypoplasia of the optic nerve
HP:0011098	Speech apraxia
HP:0012741	Unilateral cryptorchidism
HP:0030680	Abnormal cardiovascular system morphology

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000175_4	Height	2.000000e-09
GCST012226_795	Waist circumference adjusted for body mass index	3.000000e-16
GCST012227_336	Hip circumference adjusted for BMI	2.000000e-13
GCST90020028_1368	Hip circumference adjusted for BMI	6.000000e-19

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563524	NF1 Microdeletion Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression, increases methylation	1
trichostatin A	affects expression	1
sodium arsenite	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Caffeine	increases phosphorylation	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Lead	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9QR	Ubigene HEK293 RNF135 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder