TNRC6A

Summary

TNRC6A (trinucleotide repeat containing adaptor 6A, HGNC:11969) is a protein-coding gene on chromosome 16p12.1, encoding Trinucleotide repeat-containing gene 6A protein (Q8NDV7). Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs).

This gene encodes a member of the trinucleotide repeat containing 6 protein family. The protein functions in post-transcriptional gene silencing through the RNA interference (RNAi) and microRNA pathways. The protein associates with messenger RNAs and Argonaute proteins in cytoplasmic bodies known as GW-bodies or P-bodies. Inhibiting expression of this gene delocalizes other GW-body proteins and impairs RNAi and microRNA-induced gene silencing.

Source: NCBI Gene 27327 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epilepsy, familial adult myoclonic, 6 (Limited, GenCC)
• GWAS associations: 27
• Clinical variants (ClinVar): 336 total — 1 pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_014494

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11969
Approved symbol	TNRC6A
Name	trinucleotide repeat containing adaptor 6A
Location	16p12.1
Locus type	gene with protein product
Status	Approved
Aliases	CAGH26, KIAA1460, GW182
Ensembl gene	ENSG00000090905
Ensembl biotype	protein_coding
OMIM	610739
Entrez	27327

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 12 protein_coding, 9 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000315183, ENST00000395799, ENST00000450465, ENST00000462400, ENST00000464539, ENST00000477487, ENST00000491718, ENST00000561726, ENST00000562829, ENST00000563201, ENST00000566108, ENST00000567232, ENST00000568750, ENST00000568806, ENST00000568903, ENST00000569098, ENST00000569376, ENST00000569634, ENST00000895467, ENST00000938481, ENST00000938482, ENST00000938483, ENST00000938484, ENST00000938485, ENST00000949507

RefSeq mRNA: 3 — MANE Select: NM_014494 NM_001330520, NM_001351850, NM_014494

CCDS: CCDS10624, CCDS81959

Canonical transcript exons

ENST00000395799 — 25 exons

Exon	Start	End
ENSE00001621650	24750726	24750813
ENSE00001635133	24776933	24777358
ENSE00001776153	24758339	24758360
ENSE00003464287	24822874	24823013
ENSE00003484221	24797915	24797966
ENSE00003489228	24794544	24794719
ENSE00003497843	24793473	24793649
ENSE00003501412	24822077	24822147
ENSE00003517133	24795907	24795939
ENSE00003519261	24823432	24826218
ENSE00003526885	24816816	24816956
ENSE00003531845	24806206	24806283
ENSE00003546524	24789232	24791817
ENSE00003559360	24797490	24797570
ENSE00003576136	24806574	24806784
ENSE00003585004	24818593	24818700
ENSE00003587067	24820139	24820360
ENSE00003591333	24729651	24729846
ENSE00003603762	24804177	24804319
ENSE00003614563	24815147	24815305
ENSE00003621760	24805605	24805733
ENSE00003631695	24805014	24805151
ENSE00003633287	24804705	24804851
ENSE00003636094	24730253	24730300
ENSE00003692992	24809350	24809481

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 96.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.5276 / max 189.5829, expressed in 1812 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153248	11.3037	1745
153247	8.2591	1775
153250	1.2063	689
153249	0.6617	323
153246	0.5345	185
153245	0.3073	115
153240	0.2550	113

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	96.95	gold quality
calcaneal tendon	UBERON:0003701	96.32	gold quality
sural nerve	UBERON:0015488	96.04	gold quality
adrenal tissue	UBERON:0018303	95.76	gold quality
cerebellum	UBERON:0002037	94.97	gold quality
cerebellar hemisphere	UBERON:0002245	94.96	gold quality
cerebellar cortex	UBERON:0002129	94.95	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.80	gold quality
pituitary gland	UBERON:0000007	94.65	gold quality
endometrium	UBERON:0001295	94.33	gold quality
mucosa of stomach	UBERON:0001199	94.29	gold quality
left ovary	UBERON:0002119	93.93	gold quality
adenohypophysis	UBERON:0002196	93.80	gold quality
ovary	UBERON:0000992	93.67	gold quality
right ovary	UBERON:0002118	93.60	gold quality
body of uterus	UBERON:0009853	93.58	gold quality
apex of heart	UBERON:0002098	93.35	gold quality
right adrenal gland	UBERON:0001233	93.17	gold quality
right adrenal gland cortex	UBERON:0035827	93.11	gold quality
adrenal gland	UBERON:0002369	92.92	gold quality
descending thoracic aorta	UBERON:0002345	92.90	gold quality
myometrium	UBERON:0001296	92.74	gold quality
ascending aorta	UBERON:0001496	92.59	gold quality
right uterine tube	UBERON:0001302	92.58	gold quality
thoracic aorta	UBERON:0001515	92.58	gold quality
body of pancreas	UBERON:0001150	92.54	gold quality
left adrenal gland	UBERON:0001234	92.50	gold quality
uterine cervix	UBERON:0000002	92.45	gold quality
left adrenal gland cortex	UBERON:0035825	92.44	gold quality
colonic epithelium	UBERON:0000397	92.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

Literature-anchored findings (GeneRIF, showing 40)

• GW ribonucleoprotein complex is involved in the posttranscriptional regulation of gene expression (PMID:11950943)
• gene knockdown of GW182 led to the disappearance of GW bodies demonstrating that GW182 is a critical component of GW bodies (PMID:15494374)
• data support a model in which GW182 and/or the microenvironment of the cytoplasmic GWBs contribute to the RNA-induced silencing complex and to RNA silencing (PMID:16284622)
• results support a functional link between GW182 and the ability of a microRNA to repress expression of a target mRNA (PMID:16284623)
• findings show that miRNA function is effected by AGO1-GW182 complexes and the role of GW182 in silencing goes beyond promoting deadenylation (PMID:18345015)
• Data show that siRNA transfection induces up-regulated expression of both GW182, a key P-body component, and Ago2, indicating that P-body localization and interaction with GW182 and Ago2 are important in siRNA-mediated RNAi. (PMID:18946079)
• A novel 210-kDa isoform of human GW182, provisionally named trinucleotide GW1 (TNGW1)was reported.TNGW1 was expressed independently of GW182 and was present in human testis and various human cancer cells. (PMID:19056672)
• Tethering the C-terminal half of Ago2 to the 3’-UTR of reporter mRNA recapitulated translational repression comparable to that of tethered Ago2, and this repression was greatly impaired upon GW182 knockdown. (PMID:19324964)
• Our findings indicate that TNRC6A, is recruited to miRNA targets through an interaction between their N-terminal domain and an Argonaute protein (PMID:19383768)
• Structural basis of binding of P-body-associated proteins GW182 and ataxin-2 by the Mlle domain of poly(A)-binding protein.( (PMID:20181956)
• data indicate that frameshift mutations in AGO2 and TNRC6A and their losses of expression are common in GCs and CRCs with MSI-H, and suggest that these alterations may contribute to the cancer development by deregulating miRNA regulation. (PMID:20198652)
• over-expression of Ago2 and TNRC6A may be related to miRNA functions and might play a role in tumorigenesis of prostate carcinomas and esophageal squamous cell carcinomas. (PMID:20402672)
• Alanine substitution showed that GW/WG motifs in Delta12 (Delta12a, amino acids 896-1045) were important for the silencing activity of GW182. (PMID:21131274)
• Data demonstrate that in human and Drosophila melanogaster cells, the critical repressive features of both the N-terminal and C-terminal effector domains of GW182 proteins are Gly/Ser/Thr-Trp (G/S/TW) or Trp-Gly/Ser/Thr (WG/S/T) motifs. (PMID:21984184)
• Data suggest that GW182 serves as both a platform that recruits deadenylases and as a deadenylase coactivator that facilitates the removal of the poly(A) tail by CCR4-NOT. (PMID:21984185)
• Mammalian GW proteins have distinctive functions in the miRNA pathway, with GW220/TNGW1 being essential for aggregation and formation of GW/P bodies that sequester and stabilize translationally repressed target mRNA. (PMID:22891262)
• HSP90 and GW182 are important factors in the pathomechanism of alcohol-induced augmentation of HCV replication. (PMID:22898980)
• we have identified a new function of GW182 in protecting mature miRNA from being degraded by interacting with Argonaute (AGO) proteins (PMID:23090477)
• Analysis of the results suggested that TNRC6A plays an important role in navigating Argonaute protein into the nucleus to lead miRNA-mediated gene silencing. (PMID:23150874)
• GW182 plays a critical role in miRNA-mediated gene silencing. (Review) (PMID:23224966)
• GW182 proteins function as scaffold proteins for the assembly of the multiprotein complex that silences miRNA targets. (Review) (PMID:23224969)
• 28.6% of patients containing autoantibodies to the trinucleotide repeat region of the TNRC6A were shown to have a single nucleotide polymorphism at c.344C>A in the CAG/CCA/G-rich region of TNRC6A. (PMID:23224974)
• Sinse Argonaute and GW182 are the core proteins of the RNA-silencing complex (RISC), it seems appropriate to suggest that the RISC is the main target of human autoantibodies. (Review) (PMID:23224975)
• TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6. (PMID:24778252)
• The results indicate that TNRC6A subcellular localization is substantially controlled by the interaction with Argonaute proteins. (PMID:26446993)
• miRNAs, AGOs, GW182, the CCR4-NOT complex, and DDX6/Me31B repress and degrade polyadenylated mRNA targets that are translated via scanning-independent mechanisms in both human and Drosophila melanogaster cells (PMID:27009120)
• The results suggest that overexpressed Dcp1a and GW182 can form different cytoplasmic aggregates and play distinct biological roles in the miRNA pathway. (PMID:28488892)
• In miRNA-mediated gene silencing, the physical interaction between human Argonaute (hAgo) and GW182 (hGW182) is essential for facilitating the downstream silencing of the targeted mRNA. hGW182 can recruit up to three copies of hAgo via its three GW motifs. This may explain the observed cooperativity in miRNA-mediated gene silencing. (PMID:28781232)
• Functional analysis implicates TNRC6A, NAT10, MED14, and WDR5 in RNA-mediated transcriptional activation. (PMID:28813667)
• that the interactions observed between TNRC6A and importin-alpha are conserved between mouse and human complexes. Our results highlight the ability of monopartite cNLS sequences to maximise contacts at the importin-alpha major binding site, as well as regions outside the main binding cavities (PMID:28837617)
• The structure of GW182 protein silencing domain, including RNA recognition motif. (PMID:29080206)
• Study results demonstrate that TNRC6A regulates the biogenesis of the circRNA circ0006916, which regulates lung cancer cells proliferation by binding to miR-522-3p and inhibiting PHLPP1 activity. (PMID:29726904)
• Besides the role of GW182 as part of repressor complexes inside the cell, they function in wide variety of cellular processes including pathogenesis, circadian rhythm and cell cycle. (Review) (PMID:29791863)
• we report the important roles of GW182 and DDX6, but not Dicer, Ago2 and DCP1A, in PB formation, and that Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic infection reduces PB formation through several specific interactions with viral RNA-binding protein ORF57 (PMID:31400113)
• Expression of TNRC6 (GW182) Proteins Is Not Necessary for Gene Silencing by Fully Complementary RNA Duplexes. (PMID:31670606)
• DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A. (PMID:33040085)
• Identification of Phosphorylated Amino Acids in Human TNRC6A C-Terminal Region and Their Effects on the Interaction with the CCR4-NOT Complex. (PMID:33668648)
• Acute necrotizing encephalopathy-linked mutations in Nup358 impair interaction of Nup358 with TNRC6/GW182 and miRNA function. (PMID:33962210)
• Impact of scaffolding protein TNRC6 paralogs on gene expression and splicing. (PMID:34108231)
• N-terminal Ago-binding domain of GW182 contains a tryptophan-rich region that confer binding to the CCR4-NOT complex. (PMID:35822830)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnrc6a	ENSDARG00000079688
mus_musculus	Tnrc6a	ENSMUSG00000052707
rattus_norvegicus	Tnrc6a	ENSRNOG00000024737

Paralogs (5): TNRC6C (ENSG00000078687), TNRC6B (ENSG00000100354), UBAC1 (ENSG00000130560), UBXN4 (ENSG00000144224), UBXN1 (ENSG00000162191)

Protein

Protein identifiers

Trinucleotide repeat-containing gene 6A protein — Q8NDV7 (reviewed: Q8NDV7)

Alternative names: CAG repeat protein 26, EMSY interactor protein, GW182 autoantigen, Glycine-tryptophan protein of 182 kDa

All UniProt accessions (6): Q8NDV7, H3BRT3, H3BTQ1, H7C269, I3L218, I3L3S5

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent repression of translation and for siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As a scaffolding protein, associates with argonaute proteins bound to partially complementary mRNAs, and can simultaneously recruit CCR4-NOT and PAN deadenylase complexes.

Subunit / interactions. Interacts with AGO2. Interacts with AGO1, AGO3 and AGO4. Interacts with CNOT1; the interaction is direct and mediates the association with the CCR4-NOT complex. Interacts with ZC3H12A. Interacts with SND1. Interacts with GARRE1. (Microbial infection) Interacts with human herpesvirus 8 protein MTA/ORF57; this interaction inhibits P-body formation.

Subcellular location. Cytoplasm. P-body.

Tissue specificity. Ubiquitous.

Disease relevance. Epilepsy, familial adult myoclonic, 6 (FAME6) [MIM:618074] A form of familial myoclonic epilepsy, a neurologic disorder characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom. Some patients exhibit mild cognitive impairment. FAME6 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Induction. By exogenous short interfering RNA (siRNA).

Miscellaneous. Antibodies against TNRC6A are found in sera from patients with Sjoegren syndrome (SS), ataxia and sensor neuropathy diseases that developed autoantibodies against protein of the GWB structure. Autoantibodies were mapped to the GW-rich mid-part, the non-GW-rich region and the C-terminus of the protein.

Similarity. Belongs to the GW182 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q8NDV7-1	1, TNGW1	yes
Q8NDV7-2	2
Q8NDV7-3	3
Q8NDV7-4	4
Q8NDV7-5	5
Q8NDV7-6	6

RefSeq proteins (3): NP_001317449, NP_001338779, NP_055309* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR019486	Argonaute_hook_dom	Domain
IPR032226	TNRC6_PABC-bd	Domain
IPR034924	TNRC6A_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR052068	GW182_domain	Family

Pfam: PF10427, PF16608

UniProt features (81 total): compositionally biased region 28, region of interest 23, modified residue 9, splice variant 6, mutagenesis site 5, sequence variant 4, sequence conflict 3, chain 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7RUP	X-RAY DIFFRACTION	1.23
5W6V	X-RAY DIFFRACTION	2.83

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NDV7-F1	38.31	0.06

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 (9): 739, 878, 991, 1212, 1270, 1470, 1585, 1869, 1890

Mutagenesis-validated functional residues (5):

Position	Phenotype
313	does not impair interaction with ago2; when associated with a-345; a-370; a-420 and a-483.
345	does not impair interaction with ago2; when associated with a-313; a-370; a-420 and a-483.
370	does not impair interaction with ago2; when associated with a-313; a-345; a-420 and a-483.
420	does not impair interaction with ago2; when associated with a-313; a-345; a-370 and a-483.
483	does not impair interaction with ago2; when associated with a-313; a-345; a-370 and a-420.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-165159	MTOR signalling
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559585	Oncogene Induced Senescence
R-HSA-4086398	Ca2+ pathway
R-HSA-426496	Post-transcriptional silencing by small RNAs
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-8934593	Regulation of RUNX1 Expression and Activity
R-HSA-8936459	RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
R-HSA-8943723	Regulation of PTEN mRNA translation
R-HSA-8948700	Competing endogenous RNAs (ceRNAs) regulate PTEN translation
R-HSA-8986944	Transcriptional Regulation by MECP2
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9022692	Regulation of MECP2 expression and activity
R-HSA-9029569	NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux
R-HSA-9759811	Regulation of CDH11 mRNA translation by microRNAs
R-HSA-9764562	Regulation of CDH1 mRNA translation by microRNAs
R-HSA-9768778	Regulation of NPAS4 mRNA translation
R-HSA-9824594	Regulation of MITF-M-dependent genes involved in apoptosis
R-HSA-9839394	TGFBR3 expression
R-HSA-9909620	Regulation of PD-L1(CD274) translation

MSigDB gene sets: 340 (showing top): FXR_IR1_Q6, REACTOME_SIGNALING_BY_NOTCH, AP1_01, GOBP_P_BODY_ASSEMBLY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, RORA1_01, TGCACTT_MIR519C_MIR519B_MIR519A, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TATTATA_MIR374, LHX3_01, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS

GO Biological Process (8): endoderm development (GO:0007492), cellular response to starvation (GO:0009267), P-body assembly (GO:0033962), miRNA-mediated post-transcriptional gene silencing (GO:0035195), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), positive regulation of nuclear-transcribed mRNA poly(A) tail shortening (GO:0060213), regulation of translation (GO:0006417), regulatory ncRNA-mediated gene silencing (GO:0031047)

GO Molecular Function (4): RNA binding (GO:0003723), protein-macromolecule adaptor activity (GO:0030674), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (6): P-body (GO:0000932), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), cytosol (GO:0005829), RISC complex (GO:0016442), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Cellular Senescence	2
Gene Silencing by RNA	2
Generic Transcription Pathway	2
Transcriptional regulation by RUNX1	2
Signal Transduction	1
Pre-NOTCH Expression and Processing	1
Beta-catenin independent WNT signaling	1
Transcriptional Regulation by TP53	1
MAPK family signaling cascades	1
PTEN Regulation	1
Regulation of PTEN mRNA translation	1
ESR-mediated signaling	1
Transcriptional Regulation by MECP2	1
NR1H2 and NR1H3-mediated signaling	1
Regulation of CDH11 Expression and Function	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
cytoplasm	2
tissue development	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
membraneless organelle assembly	1
regulatory ncRNA-mediated post-transcriptional gene silencing	1
negative regulation of translation	1
miRNA-mediated post-transcriptional gene silencing	1
nuclear-transcribed mRNA poly(A) tail shortening	1
regulation of nuclear-transcribed mRNA poly(A) tail shortening	1
positive regulation of mRNA catabolic process	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
negative regulation of gene expression	1
nucleic acid binding	1
protein binding	1
molecular adaptor activity	1
cytoplasmic ribonucleoprotein granule	1
nuclear lumen	1
endomembrane system	1
intracellular membrane-bounded organelle	1
RNAi effector complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1402 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNRC6A	AGO2	Q9UKV8	998
TNRC6A	AGO1	Q9UL18	998
TNRC6A	DICER1	Q9UPY3	989
TNRC6A	CNOT1	A5YKK6	986
TNRC6A	PABPC1	P11940	985
TNRC6A	DDX6	P26196	979
TNRC6A	XRN1	Q8IZH2	973
TNRC6A	PIWIL1	Q96J94	955
TNRC6A	DCP1A	Q9NPI6	942
TNRC6A	CNOT9	Q92600	939
TNRC6A	TARBP2	Q15633	935
TNRC6A	PIWIL4	Q7Z3Z4	932
TNRC6A	AGO4	Q9HCK5	881
TNRC6A	FMR1	Q06787	822
TNRC6A	EDC3	Q96F86	793

IntAct

287 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
TNRC6A	AGO2	psi-mi:“MI:0914”(association)	0.960
TNRC6A	AGO2	psi-mi:“MI:0915”(physical association)	0.960
TNRC6A	AGO2	psi-mi:“MI:0403”(colocalization)	0.960
TNRC6A	AGO2	psi-mi:“MI:2364”(proximity)	0.960
AGO2	TNRC6A	psi-mi:“MI:0403”(colocalization)	0.960
AGO2	TNRC6A	psi-mi:“MI:0915”(physical association)	0.960
AGO1	TNRC6A	psi-mi:“MI:0914”(association)	0.900
TNRC6A	AGO1	psi-mi:“MI:0915”(physical association)	0.900
TNRC6A	AGO1	psi-mi:“MI:0403”(colocalization)	0.900
AGO2	DDX6	psi-mi:“MI:0914”(association)	0.810
TNRC6A	AGO4	psi-mi:“MI:0915”(physical association)	0.770
TNRC6A	AGO4	psi-mi:“MI:0403”(colocalization)	0.770
AGO4	TNRC6A	psi-mi:“MI:0915”(physical association)	0.770
AGO3	TNRC6A	psi-mi:“MI:0915”(physical association)	0.740
AGO3	TNRC6A	psi-mi:“MI:0403”(colocalization)	0.740
TNRC6A	AGO3	psi-mi:“MI:0915”(physical association)	0.740
TNRC6A	AGO3	psi-mi:“MI:0403”(colocalization)	0.740

BioGRID (434): TNRC6A (Two-hybrid), CNOT1 (Reconstituted Complex), CNOT3 (Reconstituted Complex), CNOT6L (Reconstituted Complex), CNOT7 (Reconstituted Complex), CNOT10 (Reconstituted Complex), PABPC1 (Reconstituted Complex), PAN2 (Reconstituted Complex), CNOT1 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT6L (Affinity Capture-Western), CNOT7 (Affinity Capture-Western), CNOT10 (Affinity Capture-Western), PABPC1 (Affinity Capture-Western), CNOT1 (Affinity Capture-MS)

ESM2 similar proteins: A0A087WPF7, A0JNC2, E7F1H9, O09000, O57539, O70305, P0C6A2, P15881, P15884, P51514, P70365, Q13495, Q14157, Q15596, Q15788, Q3UHC0, Q3UHK8, Q4PJW2, Q5SFM8, Q5T6F2, Q5ZL54, Q60722, Q61026, Q61286, Q62655, Q6T264, Q80TM6, Q80X50, Q86YP4, Q8BKI2, Q8CHY6, Q8NDV7, Q8SY33, Q8VHR5, Q8WXI9, Q91VX2, Q92585, Q96JK9, Q99081, Q99700

Diamond homologs: Q3UHC0, Q3UHK8, Q8BKI2, Q8NDV7, Q9HCJ0, Q9UPQ9, Q8SY33

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TRIM65	“down-regulates quantity by destabilization”	TNRC6A	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 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
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	8	42.0×	2e-09
Deadenylation of mRNA	9	39.9×	3e-10
M-decay: degradation of maternal mRNAs by maternally stored factors	9	29.7×	2e-09
MicroRNA (miRNA) biogenesis	5	23.1×	7e-05
Assembly and cell surface presentation of NMDA receptors	7	17.9×	9e-06
Nuclear events stimulated by ALK signaling in cancer	5	16.5×	3e-04
Transcriptional Regulation by MECP2	5	16.0×	3e-04
Neurexins and neuroligins	8	15.9×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA poly(A) tail shortening	9	53.9×	3e-11
pre-miRNA processing	5	41.9×	1e-05
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	5	41.9×	1e-05
miRNA-mediated gene silencing by inhibition of translation	6	39.7×	2e-06
protein localization to synapse	6	34.3×	4e-06
regulatory ncRNA-mediated gene silencing	6	30.2×	7e-06
establishment or maintenance of epithelial cell apical/basal polarity	5	21.7×	2e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	5	18.5×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	271
Likely benign	12
Benign	12

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
559390	TNRC6A, 5-BP INS, TTTCA(n) REPEAT EXPANSION	Pathogenic

SpliceAI

4186 predictions. Top by Δscore:

Variant	Effect	Δscore
16:24750691:ATTTT:A	acceptor_gain	1.0000
16:24750796:G:GT	donor_gain	1.0000
16:24776924:T:A	acceptor_gain	1.0000
16:24776925:G:A	acceptor_gain	1.0000
16:24794530:A:AG	acceptor_gain	1.0000
16:24797486:A:AG	acceptor_gain	1.0000
16:24797486:AAAG:A	acceptor_gain	1.0000
16:24797486:AAAGG:A	acceptor_gain	1.0000
16:24797487:A:G	acceptor_gain	1.0000
16:24797912:CA:C	acceptor_loss	1.0000
16:24797912:CAG:C	acceptor_gain	1.0000
16:24797913:A:AG	acceptor_gain	1.0000
16:24797913:A:AT	acceptor_loss	1.0000
16:24797913:AGA:A	acceptor_gain	1.0000
16:24797914:G:GT	acceptor_gain	1.0000
16:24797914:GA:G	acceptor_gain	1.0000
16:24797914:GAG:G	acceptor_gain	1.0000
16:24797914:GAGA:G	acceptor_gain	1.0000
16:24797966:GGTAA:G	donor_loss	1.0000
16:24797967:G:GA	donor_loss	1.0000
16:24797968:T:A	donor_loss	1.0000
16:24804316:TAAGG:T	donor_loss	1.0000
16:24804320:G:GA	donor_loss	1.0000
16:24804320:G:GG	donor_gain	1.0000
16:24805009:TATA:T	acceptor_loss	1.0000
16:24805010:A:AG	acceptor_gain	1.0000
16:24805010:ATAG:A	acceptor_loss	1.0000
16:24805011:T:G	acceptor_gain	1.0000
16:24805011:TA:T	acceptor_loss	1.0000
16:24805011:TAGAA:T	acceptor_gain	1.0000

AlphaMissense

12963 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:24791664:T:A	W1008R	1.000
16:24791664:T:C	W1008R	1.000
16:24791666:G:C	W1008C	1.000
16:24791666:G:T	W1008C	1.000
16:24809421:T:A	W1538R	1.000
16:24809421:T:C	W1538R	1.000
16:24816818:T:C	F1612L	1.000
16:24816819:T:C	F1612S	1.000
16:24816820:T:A	F1612L	1.000
16:24816820:T:G	F1612L	1.000
16:24816836:T:A	W1618R	1.000
16:24816836:T:C	W1618R	1.000
16:24816838:G:C	W1618C	1.000
16:24816838:G:T	W1618C	1.000
16:24822122:T:C	L1783P	1.000
16:24822128:T:A	L1785Q	1.000
16:24822128:T:C	L1785P	1.000
16:24822137:T:A	L1788H	1.000
16:24822137:T:C	L1788P	1.000
16:24822881:G:A	G1794D	1.000
16:24822890:T:A	L1797Q	1.000
16:24822890:T:C	L1797P	1.000
16:24822893:G:C	R1798P	1.000
16:24822899:T:A	L1800Q	1.000
16:24822899:T:C	L1800P	1.000
16:24822901:T:C	C1801R	1.000
16:24822902:G:A	C1801Y	1.000
16:24822903:C:G	C1801W	1.000
16:24822913:G:C	G1805R	1.000
16:24822914:G:A	G1805D	1.000

dbSNP variants (sampled 300 via entrez): RS1000004791 (16:24807686 G>T), RS1000018929 (16:24739260 C>T), RS1000023206 (16:24700246 T>A,G), RS1000027513 (16:24725127 A>G), RS1000049551 (16:24660238 T>C), RS1000072324 (16:24781608 G>A), RS1000090283 (16:24680683 T>C,G), RS1000096753 (16:24659577 G>A,C), RS1000106428 (16:24611960 G>A), RS1000145248 (16:24806940 A>G), RS1000145517 (16:24771519 G>A), RS1000148269 (16:24618551 C>T), RS1000158482 (16:24642100 G>A,C), RS1000171858 (16:24717857 T>C), RS1000172549 (16:24761144 C>G)

Disease associations

OMIM: gene MIM:610739 | disease phenotypes: MIM:618074, MIM:607174

GenCC curated gene-disease

Disease	Classification	Inheritance
epilepsy, familial adult myoclonic, 6	Limited	Unknown

Mondo (2): epilepsy, familial adult myoclonic, 6 (MONDO:0054846), familial meningioma (MONDO:0011789)

Orphanet (1): Familial multiple meningioma (Orphanet:263662)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001249	Intellectual disability
HP:0001336	Myoclonus
HP:0002197	Generalized-onset seizure
HP:0002315	Headache
HP:0002353	EEG abnormality
HP:0002378	Hand tremor
HP:0003581	Adult onset
HP:0007359	Focal-onset seizure
HP:0033054	Myoclonic tremor
HP:0100576	Amaurosis fugax

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST001843_1	Type 2 diabetes (dietary heme iron intake interaction)	5.000000e-06
GCST005316_508	Intelligence (MTAG)	6.000000e-10
GCST005316_509	Intelligence (MTAG)	2.000000e-09
GCST006228_12	Systolic blood pressure	1.000000e-08
GCST006230_7	Pulse pressure	2.000000e-08
GCST006269_703	General cognitive ability	1.000000e-09
GCST006944_57	Experiencing mood swings	5.000000e-08
GCST006976_86	Macular thickness	3.000000e-09
GCST007096_88	Pulse pressure	8.000000e-08
GCST007099_75	Systolic blood pressure	9.000000e-09
GCST007267_228	Systolic blood pressure	1.000000e-13
GCST007269_289	Pulse pressure	3.000000e-10
GCST007328_40	Alcohol consumption (drinks per week)	6.000000e-10
GCST007611_6	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	1.000000e-08
GCST008757_27	Alcohol consumption	1.000000e-10
GCST008811_17	Alcohol consumption (drinks per week)	4.000000e-09
GCST009524_188	Household income (MTAG)	1.000000e-08
GCST009602_75	Metabolic syndrome	1.000000e-08
GCST010546_30	Problematic alcohol use	2.000000e-08
GCST010703_260	Brain morphology (MOSTest)	2.000000e-13
GCST010988_40	Adult body size	3.000000e-13
GCST010989_7	Body size at age 10	2.000000e-10
GCST011703_24	Smoking initiation	1.000000e-08
GCST012228_506	Waist-hip index	3.000000e-08
GCST012230_148	Waist-to-hip ratio adjusted for BMI	5.000000e-08
GCST90000047_264	Age at first sexual intercourse	6.000000e-12
GCST90002395_189	Mean platelet volume	6.000000e-21

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0008355	dietary heme iron intake measurement
EFO:0004337	intelligence
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0008475	mood instability measurement
EFO:0009695	household income
EFO:0000195	metabolic syndrome
EFO:0009458	alcohol use disorder measurement
EFO:0004346	neuroimaging measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0005670	smoking initiation
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537443	Meningioma, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs72768626	Toxicity	3	ethanol	Alcohol abuse

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6497759	TNRC6A		0.00	0
rs72768626	TNRC6A	3	1.50	1	ethanol

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
lead acetate	affects cotreatment, increases expression	1
arsenite	affects binding, decreases reaction	1
zinc protoporphyrin	affects cotreatment, increases expression	1
sodium arsenite	increases abundance, increases expression	1
manganese chloride	increases expression	1
benzo(e)pyrene	affects methylation	1
gossypol acetic acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	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
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	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	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Cytarabine	increases expression	1
Formaldehyde	decreases expression	1
Manganese	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TT21	HAP1 TNRC6A (-) 1	Cancer cell line	Male
CVCL_XU63	HAP1 TNRC6A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT04386642	PHASE4	UNKNOWN	Tranexamic Acid Reduce Blood Loss in Meningioma Resection
NCT06377371	PHASE4	RECRUITING	Feasibility of Intraoperative Tracing of Meningioma Using [Cu64]DOTATATE
NCT00517959	PHASE3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01655927	PHASE3	UNKNOWN	Efficacy of Tranexamic Acid in Brain Tumor Resections
NCT03015701	PHASE3	COMPLETED	S9005 Mifepristone in Meningioma
NCT03558516	PHASE3	COMPLETED	Magnesium and Intraoperative Blood Loss in Meningioma Surgery
NCT04305470	PHASE3	COMPLETED	Gleolan for Visualization of Newly Diagnosed or Recurrent Meningioma
NCT00003483	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Meningioma
NCT00589784	PHASE2	COMPLETED	Phase II Trial of Sunitinib (SU011248) in Patients With Recurrent or Inoperable Meningioma
NCT00706810	PHASE2	COMPLETED	Combination of Hydroxyurea and Verapamil for Refractory Meningiomas
NCT00859040	PHASE2	COMPLETED	Monthly SOM230C for Recurrent or Progressive Meningioma
NCT01967823	PHASE2	COMPLETED	T Cell Receptor Immunotherapy Targeting NY-ESO-1 for Patients With NY-ESO-1 Expressing Cancer
NCT02523014	PHASE2	RECRUITING	Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib in Treating Patients With Progressive Meningiomas
NCT02648997	PHASE2	ACTIVE_NOT_RECRUITING	An Open-Label Phase II Study of Nivolumab or Nivolumab/Ipilimumab in Adult Participants With Progessive/ Recurrent Meningioma
NCT02831257	PHASE2	COMPLETED	AZD2014 In NF2 Patients With Progressive or Symptomatic Meningiomas
NCT02847559	PHASE2	RECRUITING	Optune Delivered Electric Field Therapy and Bevacizumab in Treating Patients With Recurrent or Progressive Grade 2 or 3 Meningioma
NCT03013387	PHASE2	WITHDRAWN	Dosimetry Guided PRRT With 90Y-DOTATOC
NCT03071874	PHASE2	UNKNOWN	Vistusertib (AZD2014) For Recurrent Grade II-III Meningiomas
NCT03095248	PHASE2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT03273712	PHASE2	COMPLETED	Dosimetry-Guided, Peptide Receptor Radiotherapy (PRRT) With 90Y-DOTA- tyr3-Octreotide (90Y-DOTATOC)
NCT03971461	PHASE2	ACTIVE_NOT_RECRUITING	Phase II Study of 177Lu-DOTATATE Radionuclide in Adults With Progressive or High-risk Meningioma
NCT04082520	PHASE2	RECRUITING	Lutathera for the Treatment of Inoperable, Progressive Meningioma After External Beam Radiation Therapy
NCT04298541	PHASE2	NOT_YET_RECRUITING	Direct Comparison of Ga-68-DOTATATE and Ga-68-DOTATOC
NCT04374305	PHASE2	RECRUITING	Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)
NCT04659811	PHASE2	ACTIVE_NOT_RECRUITING	Stereotactic Radiosurgery and Immunotherapy (Pembrolizumab) for the Treatment of Recurrent Meningioma
NCT05425004	PHASE2	RECRUITING	Cabozantinib for Patients With Recurrent or Progressive Meningioma
NCT05940493	PHASE2	RECRUITING	Abemaciclib in Newly Diagnosed Meningioma Patients
NCT06012929	PHASE2	WITHDRAWN	A Study of ONC201 for Refractory Meningioma
NCT06126588	PHASE2	RECRUITING	Combination of Everolimus and 177Lu-DOTATATE in the Treatment of Grades 2 and 3 Refractory Meningioma: a Phase IIb Clinical Trial
NCT06132685	PHASE2	RECRUITING	Post-Operative Dosing of Dexamethasone in Patients With Brain Tumors After a Craniotomy, PODS Trial
NCT06322342	PHASE2	COMPLETED	Phase 2 Ascending Dose Safety and Efficacy Study of RVP-001, a Manganese-based MRI Contrast Agent
NCT06326190	PHASE2	RECRUITING	177Lu-DOTATATE for Recurrent Meningioma
NCT06439420	PHASE2	COMPLETED	CBT-I in Primary Brain Tumor Patients: Phase IIc Randomized Feasibility Pilot Trial
NCT06684795	PHASE2	RECRUITING	FG001 in Subjects with Meningiomas or Presumed Low-Grade Gliomas Scheduled for Neurosurgery
NCT06710249	PHASE2	RECRUITING	Impact of Salovum® and SPC® Flakes on Brain Tumor Induced Edema
NCT06804655	PHASE2	NOT_YET_RECRUITING	Pharmacoscopy for Patients With Refractory Primary Brain Tumors
NCT07428616	PHASE2	RECRUITING	A Study of Zanzalintinib in Participants With Recurrent or Progressive Meningioma
NCT07533942	PHASE2	NOT_YET_RECRUITING	A Study of JZP3507 (ONC206) in Recurrent Grade 2 or 3 Meningioma
NCT03267836	PHASE1	TERMINATED	Neoadjuvant Avelumab and Hypofractionated Proton Radiation Therapy Followed by Surgery for Recurrent Radiation-refractory Meningioma