TNRC6B

Summary

TNRC6B (trinucleotide repeat containing adaptor 6B, HGNC:29190) is a protein-coding gene on chromosome 22q13.1, encoding Trinucleotide repeat-containing gene 6B protein (Q9UPQ9). Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). It is haploinsufficient (ClinGen: sufficient evidence).

Enables RNA binding activity. Involved in positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay; positive regulation of nuclear-transcribed mRNA poly(A) tail shortening; and regulatory ncRNA-mediated gene silencing. Acts upstream of with a positive effect on miRNA-mediated gene silencing by inhibition of translation. Predicted to be located in cytosol. Predicted to be active in P-body and nucleoplasm. Implicated in subserous uterine fibroid and uterine fibroid.

Source: NCBI Gene 23112 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 51
• Clinical variants (ClinVar): 634 total — 40 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 25
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001162501

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29190
Approved symbol	TNRC6B
Name	trinucleotide repeat containing adaptor 6B
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1093
Ensembl gene	ENSG00000100354
Ensembl biotype	protein_coding
OMIM	610740
Entrez	23112

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000301923, ENST00000335727, ENST00000402203, ENST00000446273, ENST00000454349, ENST00000467658, ENST00000489500, ENST00000497559, ENST00000878235, ENST00000878236, ENST00000878237, ENST00000921023, ENST00000921024, ENST00000921025, ENST00000949217

RefSeq mRNA: 3 — MANE Select: NM_001162501 NM_001024843, NM_001162501, NM_015088

CCDS: CCDS46712, CCDS46713, CCDS54533

Canonical transcript exons

ENST00000454349 — 23 exons

Exon	Start	End
ENSE00001662978	40281119	40281289
ENSE00003495912	40277999	40278044
ENSE00003582860	40277077	40277151
ENSE00003670787	40285645	40285770
ENSE00003693382	40279995	40280143
ENSE00003888728	40308512	40308649
ENSE00003889617	40300455	40300586
ENSE00003889762	40273425	40273600
ENSE00003889880	40246015	40246102
ENSE00003891203	40312505	40312651
ENSE00003891449	40321090	40321229
ENSE00003891687	40270122	40270280
ENSE00003892010	40315942	40316012
ENSE00003892262	40312902	40312997
ENSE00003892275	40264688	40267036
ENSE00003892414	40322854	40335808
ENSE00003892756	40315283	40315507
ENSE00003893803	40261832	40262173
ENSE00003893988	40251179	40251200
ENSE00003894039	40301150	40301333
ENSE00003895217	40310817	40310993
ENSE00003895789	40300910	40301005
ENSE00003896114	40177925	40178140

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1431 / max 416.2548, expressed in 1688 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192399	6.7584	1219
192409	2.9710	1172
192398	2.0099	824
192396	0.9523	485
192417	0.5549	219
192397	0.4484	108
192408	0.2352	88
192400	0.1198	41
192401	0.0930	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.56	gold quality
epithelium of nasopharynx	UBERON:0001951	97.41	gold quality
nasopharynx	UBERON:0001728	97.39	gold quality
sural nerve	UBERON:0015488	96.44	gold quality
oocyte	CL:0000023	95.52	gold quality
caput epididymis	UBERON:0004358	94.86	gold quality
trabecular bone tissue	UBERON:0002483	94.71	gold quality
secondary oocyte	CL:0000655	94.70	gold quality
seminal vesicle	UBERON:0000998	94.63	gold quality
nipple	UBERON:0002030	94.55	gold quality
cauda epididymis	UBERON:0004360	94.17	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.00	gold quality
corpus callosum	UBERON:0002336	93.88	gold quality
calcaneal tendon	UBERON:0003701	93.82	gold quality
superior vestibular nucleus	UBERON:0007227	93.73	gold quality
ventral tegmental area	UBERON:0002691	93.67	gold quality
corpus epididymis	UBERON:0004359	93.65	gold quality
mammary duct	UBERON:0001765	93.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.50	gold quality
cerebellar vermis	UBERON:0004720	93.48	gold quality
renal medulla	UBERON:0000362	93.43	gold quality
entorhinal cortex	UBERON:0002728	93.23	gold quality
trigeminal ganglion	UBERON:0001675	93.15	gold quality
inferior vagus X ganglion	UBERON:0005363	93.11	gold quality
colonic epithelium	UBERON:0000397	92.99	gold quality
bronchial epithelial cell	CL:0002328	92.94	gold quality
superior surface of tongue	UBERON:0007371	92.93	gold quality
pylorus	UBERON:0001166	92.76	gold quality
pons	UBERON:0000988	92.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.37	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-97	no	1521.16
E-MTAB-6911	no	527.24
E-MTAB-7606	no	283.78
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

816 targeting TNRC6B, 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-MIR-3163	100.00	77.23	8605
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 12)

• Our findings indicate that TNRC6B, is recruited to miRNA targets through an interaction between their N-terminal domain and an Argonaute protein (PMID:19383768)
• single nucleotide polymorphisms in the TNRC6B gene is associated with uterine fibroid. (PMID:23604678)
• Trinucleotide repeat containing 6B (TNRC6B) rs12484776 associated with uterine fibroid volume in european americans. (PMID:23892540)
• The rs12484776 significantly contributes to uterine myoma risk among Saudi women, both in single and also in synergistic cooperation with rs2280543, rs7913069, and rs1056836 markers. (PMID:27987337)
• Methylation of three CpGs (DROSHA: cg23230564, TNRC6B: cg06751583, and TNRC6B: cg21034183) was prospectively associated with time to cancer development (positively for cg06751583, inversely for cg23230564 and cg21034183), whereas methylation of one CpG site (DROSHA: cg16131300) was positively associated with cancer prevalence. (PMID:29475968)
• both BET1L and TNRC6B contributed to the risk of UL in Chinese women (PMID:29743541)
• The TNRC6 proteins bind to the 5’end of HCV RNA in a miR-122-dependent fashion and contribute functionally to replication of the viral genome by spatially regulating binding of miR-122/Ago2 to the 5’UTR. (PMID:30997501)
• Expression of TNRC6 (GW182) Proteins Is Not Necessary for Gene Silencing by Fully Complementary RNA Duplexes. (PMID:31670606)
• Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD. (PMID:32152250)
• FOXA1-induced LINC01207 facilitates head and neck squamous cell carcinoma via up-regulation of TNRC6B. (PMID:32450521)
• Impact of scaffolding protein TNRC6 paralogs on gene expression and splicing. (PMID:34108231)
• Novel variants in TNRC6B cause global developmental delay with speech and behavioral abnormalities, short stature, low body weight, cafe-au-lait spots, and metabolic abnormality. (PMID:38404251)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnrc6ba	ENSDARG00000074161
danio_rerio	tnrc6bb.2	ENSDARG00000076389
danio_rerio	tnrc6bb.1	ENSDARG00000079723
mus_musculus	Tnrc6b	ENSMUSG00000047888
rattus_norvegicus	Tnrc6b	ENSRNOG00000024907

Paralogs (5): TNRC6C (ENSG00000078687), TNRC6A (ENSG00000090905), UBAC1 (ENSG00000130560), UBXN4 (ENSG00000144224), UBXN1 (ENSG00000162191)

Protein

Protein identifiers

Trinucleotide repeat-containing gene 6B protein — Q9UPQ9 (reviewed: Q9UPQ9)

All UniProt accessions (2): Q9UPQ9, H0Y720

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 translational repression and siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As scaffolding protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes.

Subunit / interactions. Interacts with AGO1, AGO2, AGO3 and AGO4. Interacts with CNOT1; the interaction mediates the association with the CCR4-NOT complex. Interacts with PAN3; the interaction mediates the association with the PAN complex. Interacts with MOV10; the interaction is direct and RNA-dependent.

Subcellular location. Cytoplasm. P-body.

Disease relevance. Global developmental delay with speech and behavioral abnormalities (GDSBA) [MIM:619243] An autosomal dominant disorder manifesting in infancy or early childhood. It is characterized by mildly delayed fine and motor skills, mildly impaired intellectual development, speech and language delay, and variable behavioral abnormalities, mostly autism and attention deficit-hyperactivity disorder. Additional non-specific features include facial dysmorphism, myopia or strabismus, and skeletal defects. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the GW182 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UPQ9-3	1	yes
Q9UPQ9-1	2
Q9UPQ9-2	3

RefSeq proteins (3): NP_001020014, NP_001155973, NP_055903 (=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
IPR034925	TNRC6B_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR052068	GW182_domain	Family

Pfam: PF10427, PF16608

UniProt features (65 total): compositionally biased region 31, region of interest 12, modified residue 7, sequence variant 7, splice variant 4, chain 1, domain 1, coiled-coil region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UPQ9-F1	39.58	0.05

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 (7): 879, 1432, 1449, 1461, 1464, 1816, 1832

Function

Pathways and Gene Ontology

Reactome pathways

23 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-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: 636 (showing top): GCACCTT_MIR18A_MIR18B, AGGAAGC_MIR5163P, REACTOME_SIGNALING_BY_NOTCH, GGTGTGT_MIR329, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, ATACCTC_MIR202, GTCTACC_MIR379, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, CTATGCA_MIR153, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, ATGTTAA_MIR302C

GO Biological Process (6): regulatory ncRNA-mediated gene silencing (GO:0031047), 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), positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900153), regulation of translation (GO:0006417)

GO Molecular Function (3): RNA binding (GO:0003723), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (4): P-body (GO:0000932), nucleoplasm (GO:0005654), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Cellular Senescence	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
Gene Silencing by RNA	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
positive regulation of mRNA catabolic process	2
binding	2
negative regulation of gene expression	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
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
nucleic acid binding	1
cytoplasmic ribonucleoprotein granule	1
nuclear lumen	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1376 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNRC6B	AGO2	Q9UKV8	981
TNRC6B	MOV10	Q9HCE1	978
TNRC6B	AGO1	Q9UL18	948
TNRC6B	DICER1	Q9UPY3	874
TNRC6B	TNRC6A	Q8NDV7	715
TNRC6B	AGO3	Q9H9G7	685
TNRC6B	AGO4	Q9HCK5	670
TNRC6B	BET1L	Q9NYM9	663
TNRC6B	GEMIN4	P57678	641
TNRC6B	DDX20	Q9UHI6	617
TNRC6B	DROSHA	Q9NRR4	561
TNRC6B	CNOT7	Q9UIV1	550
TNRC6B	CNOT9	Q92600	506
TNRC6B	NCKAP1	Q9Y2A7	495
TNRC6B	DHX9	Q08211	492

IntAct

265 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
CEP97	CCP110	psi-mi:“MI:2364”(proximity)	0.950
AGO2	TNRC6B	psi-mi:“MI:0915”(physical association)	0.930
AGO2	TNRC6B	psi-mi:“MI:0403”(colocalization)	0.930
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
AGO1	TNRC6A	psi-mi:“MI:0914”(association)	0.900
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PAN3	TNRC6B	psi-mi:“MI:0915”(physical association)	0.630
TNRC6B	PAN3	psi-mi:“MI:0407”(direct interaction)	0.630
TNRC6B	PAN3	psi-mi:“MI:0915”(physical association)	0.630
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
TNRC6B	CNOT1	psi-mi:“MI:0915”(physical association)	0.580
TNRC6B	CNOT1	psi-mi:“MI:0914”(association)	0.580
CNOT1	TNRC6B	psi-mi:“MI:0915”(physical association)	0.580
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
AGO2	FKBP5	psi-mi:“MI:0914”(association)	0.530
TNRC6B	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
TNRC6B	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
TNRC6B	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
TNRC6B	APBA3	psi-mi:“MI:0407”(direct interaction)	0.440
TNRC6B	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
TNRC6B	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (423): TNRC6B (Affinity Capture-RNA), TNRC6B (Affinity Capture-MS), CNOT1 (Affinity Capture-Western), CNOT2 (Affinity Capture-Western), CNOT6 (Affinity Capture-Western), CNOT6L (Affinity Capture-Western), CNOT7 (Affinity Capture-Western), CNOT8 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), PAN3 (Affinity Capture-Western), CNOT1 (Reconstituted Complex), PAN3 (Reconstituted Complex), TNRC6B (Proximity Label-MS), TNRC6B (Affinity Capture-MS), TNRC6B (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
TNRC6B	“up-regulates activity”	AGO2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 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
MAP3K8 (TPL2)-dependent MAPK1/3 activation	6	32.4×	2e-06
Regulation of MITF-M-dependent genes involved in apoptosis	6	28.8×	2e-06
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	7	27.5×	8e-07
Regulation of RUNX1 Expression and Activity	5	25.4×	3e-05
Deadenylation of mRNA	7	23.3×	1e-06
Ras activation upon Ca2+ influx through NMDA receptor	5	21.6×	6e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	20.6×	7e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	20.6×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
pre-miRNA processing	6	37.5×	2e-06
nuclear-transcribed mRNA poly(A) tail shortening	8	35.7×	4e-08
centriole replication	8	32.6×	4e-08
miRNA-mediated gene silencing by inhibition of translation	6	29.6×	8e-06
miRNA processing	5	29.3×	6e-05
establishment or maintenance of epithelial cell apical/basal polarity	7	22.6×	5e-06
protein localization to synapse	5	21.3×	3e-04
receptor clustering	6	20.8×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	25
Uncertain significance	411
Likely benign	97
Benign	8

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048537	NM_001162501.2(TNRC6B):c.2040G>A (p.Trp680Ter)	Pathogenic
1048538	NM_001162501.2(TNRC6B):c.1879C>T (p.Gln627Ter)	Pathogenic
1048539	NM_001162501.2(TNRC6B):c.4872del (p.Trp1625fs)	Pathogenic
1048540	NM_001162501.2(TNRC6B):c.3967C>T (p.Gln1323Ter)	Pathogenic
1048541	NM_001162501.2(TNRC6B):c.3262+5G>C	Pathogenic
1048542	NM_001162501.2(TNRC6B):c.4070T>A (p.Val1357Glu)	Pathogenic
1205080	NM_001162501.2(TNRC6B):c.4551_4554del (p.Asp1518fs)	Pathogenic
1318824	NM_001162501.2(TNRC6B):c.2273dup (p.Asn758fs)	Pathogenic
1325802	NM_001162501.2(TNRC6B):c.2039G>A (p.Trp680Ter)	Pathogenic
1352931	NM_001162501.2(TNRC6B):c.1090C>T (p.Gln364Ter)	Pathogenic
1527918	NM_001162501.2(TNRC6B):c.16C>T (p.Gln6Ter)	Pathogenic
1700781	NM_001162501.2(TNRC6B):c.4974+2T>A	Pathogenic
1701441	NM_001162501.2(TNRC6B):c.1989_1990del (p.Gly665fs)	Pathogenic
1710230	NM_001162501.2(TNRC6B):c.3349_3358del (p.Gly1117fs)	Pathogenic
1801330	NM_001162501.2(TNRC6B):c.1660del (p.Gln554fs)	Pathogenic
2430083	NM_001162501.2(TNRC6B):c.2641C>T (p.Gln881Ter)	Pathogenic
2504206	NM_001162501.2(TNRC6B):c.1359_1362del (p.Glu454fs)	Pathogenic
2575176	NM_001162501.2(TNRC6B):c.830_836del (p.Asn277fs)	Pathogenic
2579964	NM_001162501.2(TNRC6B):c.1249C>T (p.Arg417Ter)	Pathogenic
2604811	NM_001162501.2(TNRC6B):c.1813C>T (p.Gln605Ter)	Pathogenic
2663281	NM_001162501.2(TNRC6B):c.2990G>A (p.Trp997Ter)	Pathogenic
2672911	NM_001162501.2(TNRC6B):c.4457G>A (p.Trp1486Ter)	Pathogenic
3180722	NM_001162501.2(TNRC6B):c.4120+1G>T	Pathogenic
3253187	NM_001162501.2(TNRC6B):c.121G>T (p.Glu41Ter)	Pathogenic
3255081	NM_001162501.2(TNRC6B):c.3193_3194del (p.Gln1065fs)	Pathogenic
3382869	NM_001162501.2(TNRC6B):c.3820C>T (p.Gln1274Ter)	Pathogenic
3773686	NM_001162501.2(TNRC6B):c.3298C>T (p.Arg1100Ter)	Pathogenic
3775098	NM_001162501.2(TNRC6B):c.2112del (p.Asn704fs)	Pathogenic
3809203	NM_001162501.2(TNRC6B):c.641dup (p.Asn214fs)	Pathogenic
3900253	NM_001162501.2(TNRC6B):c.2351dup (p.Gly784_Asn785insTer)	Pathogenic

SpliceAI

3310 predictions. Top by Δscore:

Variant	Effect	Δscore
22:40246099:GAAG:G	donor_gain	1.0000
22:40246103:GTAG:G	donor_loss	1.0000
22:40246104:T:A	donor_loss	1.0000
22:40251200:GGTAA:G	donor_loss	1.0000
22:40251201:G:A	donor_loss	1.0000
22:40251202:T:G	donor_loss	1.0000
22:40256481:C:G	donor_gain	1.0000
22:40261830:A:AG	acceptor_gain	1.0000
22:40261830:A:C	acceptor_loss	1.0000
22:40261830:AGT:A	acceptor_gain	1.0000
22:40261831:G:GT	acceptor_gain	1.0000
22:40261831:GT:G	acceptor_gain	1.0000
22:40261831:GTG:G	acceptor_gain	1.0000
22:40270120:A:AG	acceptor_gain	1.0000
22:40270121:G:GG	acceptor_gain	1.0000
22:40277074:TAG:T	acceptor_loss	1.0000
22:40277075:A:AG	acceptor_gain	1.0000
22:40277075:A:C	acceptor_loss	1.0000
22:40277075:AGT:A	acceptor_gain	1.0000
22:40277076:G:GA	acceptor_gain	1.0000
22:40277076:GT:G	acceptor_gain	1.0000
22:40277076:GTG:G	acceptor_gain	1.0000
22:40279982:T:TA	acceptor_gain	1.0000
22:40279990:TTCA:T	acceptor_loss	1.0000
22:40279991:TCA:T	acceptor_loss	1.0000
22:40279992:CAGG:C	acceptor_loss	1.0000
22:40279993:A:AC	acceptor_loss	1.0000
22:40279993:A:AG	acceptor_gain	1.0000
22:40279994:G:GG	acceptor_gain	1.0000
22:40279994:GGA:G	acceptor_gain	1.0000

AlphaMissense

12051 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:40261999:T:C	F95L	1.000
22:40262001:C:A	F95L	1.000
22:40262001:C:G	F95L	1.000
22:40266097:T:A	W623R	1.000
22:40266097:T:C	W623R	1.000
22:40266853:T:A	W875R	1.000
22:40266853:T:C	W875R	1.000
22:40266855:G:C	W875C	1.000
22:40266855:G:T	W875C	1.000
22:40266916:T:A	W896R	1.000
22:40266916:T:C	W896R	1.000
22:40266918:G:C	W896C	1.000
22:40266918:G:T	W896C	1.000
22:40308586:T:A	W1399R	1.000
22:40308586:T:C	W1399R	1.000
22:40310984:T:A	W1476R	1.000
22:40310984:T:C	W1476R	1.000
22:40312507:T:C	F1480L	1.000
22:40312508:T:C	F1480S	1.000
22:40312508:T:G	F1480C	1.000
22:40312509:C:A	F1480L	1.000
22:40312509:C:G	F1480L	1.000
22:40312525:T:A	W1486R	1.000
22:40312525:T:C	W1486R	1.000
22:40312527:G:C	W1486C	1.000
22:40312527:G:T	W1486C	1.000
22:40315987:T:A	L1650Q	1.000
22:40315987:T:C	L1650P	1.000
22:40315993:T:A	L1652H	1.000
22:40315993:T:C	L1652P	1.000

dbSNP variants (sampled 300 via entrez): RS1000001110 (22:40101474 A>G), RS1000002209 (22:40268435 G>GT), RS1000003209 (22:40317471 G>A,C), RS1000012266 (22:40187861 T>C,G), RS1000016286 (22:40138004 G>A), RS1000020138 (22:40228108 T>C,G), RS1000032344 (22:40279163 G>A), RS1000043290 (22:40188208 CA>C,CAA), RS1000055746 (22:40185642 G>A), RS1000057255 (22:40065261 C>T), RS1000087844 (22:40307840 GC>G), RS1000088199 (22:40158219 A>G), RS1000094033 (22:40234127 A>C), RS1000095341 (22:40101196 G>A,C,T), RS1000096455 (22:40060214 A>G,T)

Disease associations

OMIM: gene MIM:610740 | disease phenotypes: MIM:619243, MIM:617755

GenCC curated gene-disease

Disease	Classification	Inheritance
global developmental delay with speech and behavioral abnormalities	Strong	Autosomal dominant
syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (5): global developmental delay with speech and behavioral abnormalities (MONDO:0030995), neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MONDO:0060596), neurodevelopmental disorder (MONDO:0700092), autism spectrum disorder (MONDO:0005258), syndromic intellectual disability (MONDO:0000508)

Orphanet (2): BPTF-related intellectual disability-facial dysmorphism-skeletal anomalies syndrome (Orphanet:686482), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000494	Downslanted palpebral fissures
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000826	Precocious puberty
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001382	Joint hypermobility
HP:0002023	Anal atresia
HP:0002194	Delayed gross motor development
HP:0002360	Sleep disturbance
HP:0002558	Supernumerary nipple
HP:0007018	Attention deficit hyperactivity disorder
HP:0010862	Delayed fine motor development

GWAS associations

51 associations (top):

Study	Trait	p-value
GCST000307_1	Prostate cancer	5.000000e-07
GCST000431_4	Height	2.000000e-07
GCST001027_2	Uterine fibroids	3.000000e-12
GCST001714_3	Prostate cancer	4.000000e-06
GCST001714_4	Prostate cancer	4.000000e-07
GCST002667_12	Mammographic density (dense area)	2.000000e-13
GCST002770_2	Hand grip strength	5.000000e-06
GCST002783_136	Body mass index	4.000000e-06
GCST002783_322	Body mass index	2.000000e-06
GCST002783_601	Body mass index	7.000000e-06
GCST003453_13	Chronotype	1.000000e-08
GCST004602_302	Mean corpuscular volume	3.000000e-10
GCST004630_47	Mean corpuscular hemoglobin	2.000000e-09
GCST004633_18	Neutrophil percentage of white cells	5.000000e-09
GCST004904_211	Body mass index	2.000000e-16
GCST004904_213	Body mass index	2.000000e-15
GCST006021_37	Systolic blood pressure	7.000000e-06
GCST006022_16	Pulse pressure	2.000000e-09
GCST006462_46	Uterine fibroids	1.000000e-12
GCST006462_47	Uterine fibroids	3.000000e-13
GCST006479_85	Diverticular disease	1.000000e-06
GCST006655_11	Breast size	7.000000e-07
GCST006921_10	Regular attendance at a pub or social club	3.000000e-10
GCST007096_173	Pulse pressure	5.000000e-13
GCST007097_38	Pulse pressure	2.000000e-06
GCST007268_70	Diastolic blood pressure	4.000000e-09
GCST007269_148	Pulse pressure	1.000000e-16
GCST007565_12	Morning person	1.000000e-18
GCST007565_21	Morning person	7.000000e-17
GCST007576_40	Chronotype	1.000000e-18

EFO canonical traits (19, from GWAS)

EFO ID	Trait name
EFO:0005941	mammographic density measurement
EFO:0006503	dense area measurement
EFO:0006941	grip strength measurement
EFO:0004340	body mass index
EFO:0004527	mean corpuscular hemoglobin
EFO:0007990	neutrophil percentage of leukocytes
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0009959	diverticular disease
EFO:0009592	social interaction measurement
EFO:0006336	diastolic blood pressure
EFO:0008328	chronotype measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004471	insulin sensitivity measurement
EFO:0009131	response to polyunsaturated fatty acid supplementation
EFO:0008111	diet measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004305	erythrocyte count
EFO:0007986	reticulocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs9611280	TNRC6B		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	4
bisphenol A	decreases methylation, increases expression, affects cotreatment, decreases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
testosterone undecanoate	decreases expression, affects cotreatment	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation, decreases methylation	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
entinostat	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
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Vorinostat	decreases expression	1
Panobinostat	affects cotreatment, affects expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	increases abundance, affects cotreatment, decreases expression	1
Cadmium	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice