TNRC6C

Summary

TNRC6C (trinucleotide repeat containing adaptor 6C, HGNC:29318) is a protein-coding gene on chromosome 17q25.3, encoding Trinucleotide repeat-containing gene 6C protein (Q9HCJ0). Plays a role in RNA-mediated gene silencing by micro-RNAs (miRNAs).

Predicted to enable RNA binding activity. Involved in miRNA-mediated post-transcriptional gene silencing; positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay; and positive regulation of nuclear-transcribed mRNA poly(A) tail shortening. Predicted to be located in cytosol. Predicted to be active in P-body and nucleoplasm.

Source: NCBI Gene 57690 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 301 total
• MANE Select transcript: NM_001142640

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29318
Approved symbol	TNRC6C
Name	trinucleotide repeat containing adaptor 6C
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1582, FLJ20015
Ensembl gene	ENSG00000078687
Ensembl biotype	protein_coding
OMIM	610741
Entrez	57690

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000585438, ENST00000587990, ENST00000588061, ENST00000588549, ENST00000588847, ENST00000591851, ENST00000592251, ENST00000592566, ENST00000636222, ENST00000696270, ENST00000696541, ENST00000935185, ENST00000935186, ENST00000935187, ENST00000935188, ENST00000935189, ENST00000935190

RefSeq mRNA: 7 — MANE Select: NM_001142640 NM_001142640, NM_001395508, NM_001395509, NM_001395510, NM_001395511, NM_001395512, NM_018996

CCDS: CCDS45799, CCDS92403

Canonical transcript exons

ENST00000696270 — 23 exons

Exon	Start	End
ENSE00000745655	78093620	78093763
ENSE00000866808	78092933	78093124
ENSE00000866811	78086853	78087093
ENSE00001289500	78102474	78102544
ENSE00001289512	78098343	78098537
ENSE00001344166	78097745	78097861
ENSE00001344173	78091440	78091607
ENSE00001344179	78086503	78086586
ENSE00001667828	78083047	78083166
ENSE00001719194	78079395	78079541
ENSE00001719706	78103414	78103553
ENSE00003471016	78064722	78064937
ENSE00003528956	78067757	78067923
ENSE00003613917	78071085	78071165
ENSE00003615320	78075136	78075278
ENSE00003693490	78073037	78073094
ENSE00003792012	78004170	78004269
ENSE00003796310	78031516	78031842
ENSE00003797973	78048845	78051448
ENSE00003798274	77958703	77959268
ENSE00003798292	78104485	78108822
ENSE00003799074	78077185	78077334
ENSE00003799651	78005058	78005079

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 96.24.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9501 / max 21.1051, expressed in 509 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163023	0.3676	203
163024	0.1918	111
163021	0.1678	78
163022	0.1130	41
208389	0.1100	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.24	gold quality
calcaneal tendon	UBERON:0003701	88.01	gold quality
cerebellar vermis	UBERON:0004720	87.44	gold quality
cerebellar cortex	UBERON:0002129	86.78	gold quality
cerebellar hemisphere	UBERON:0002245	86.75	gold quality
cerebellum	UBERON:0002037	86.38	gold quality
cortical plate	UBERON:0005343	86.20	gold quality
corpus callosum	UBERON:0002336	86.10	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.09	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.01	silver quality
nerve	UBERON:0001021	85.90	gold quality
tibial nerve	UBERON:0001323	85.90	gold quality
left ventricle myocardium	UBERON:0006566	85.38	silver quality
thymus	UBERON:0002370	84.66	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.27	gold quality
bone marrow cell	CL:0002092	84.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.40	gold quality
tibialis anterior	UBERON:0001385	83.22	silver quality
popliteal artery	UBERON:0002250	83.02	gold quality
tibial artery	UBERON:0007610	83.01	gold quality
postcentral gyrus	UBERON:0002581	82.85	gold quality
tendon	UBERON:0000043	82.57	gold quality
mucosa of stomach	UBERON:0001199	82.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.15	gold quality
aorta	UBERON:0000947	82.14	gold quality
descending thoracic aorta	UBERON:0002345	81.29	gold quality
prefrontal cortex	UBERON:0000451	81.26	gold quality
ascending aorta	UBERON:0001496	81.22	gold quality
deltoid	UBERON:0001476	81.17	silver quality
thoracic aorta	UBERON:0001515	81.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.32
E-GEOD-137537	yes	7.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

201 targeting TNRC6C, 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-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-302E	99.96	70.74	2669

Literature-anchored findings (GeneRIF, showing 9)

• Through deletion and mutagenesis, study identified the C-terminal part of TNRC6C encompassing the RRM RNA-binding motif as a key effector domain mediating protein synthesis repression by TNRC6C. (PMID:19304925)
• Our findings indicate that TNRC6C, is recruited to miRNA targets through an interaction between their N-terminal domain and an Argonaute protein (PMID:19383768)
• The authors show that a conserved motif in the human GW182 paralog TNRC6C interacts with the C-terminal domain of polyadenylate binding protein 1 (PABC) and present the crystal structure of the complex. (PMID:20098421)
• These findings reveal that despite species-specific differences in the relative strength of the PABPC1-binding sites, the interaction between GW182 proteins and PABPC1 is critical for miRNA-mediated silencing in animal cells. (PMID:21063388)
• confirmed the anti-proliferative, pro-apoptotic and pro-autophagy capabilities of TNRC6C-AS1 through STK4 methylation via the Hippo signalling pathway in thyroid carcinoma (PMID:30938030)
• 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)
• Impact of scaffolding protein TNRC6 paralogs on gene expression and splicing. (PMID:34108231)
• Massively parallel reporter assays discover de novo exonic splicing mutants in paralogs of Autism genes. (PMID:35051175)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnrc6c1	ENSDARG00000076847
mus_musculus	Tnrc6c	ENSMUSG00000025571
rattus_norvegicus	Tnrc6c	ENSRNOG00000022395

Paralogs (5): TNRC6A (ENSG00000090905), TNRC6B (ENSG00000100354), UBAC1 (ENSG00000130560), UBXN4 (ENSG00000144224), UBXN1 (ENSG00000162191)

Protein

Protein identifiers

Trinucleotide repeat-containing gene 6C protein — Q9HCJ0 (reviewed: Q9HCJ0)

All UniProt accessions (5): Q9HCJ0, A0A1B0GU24, A0AAA9XYZ6, K7EKN9, K7ELY5

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in RNA-mediated gene silencing by micro-RNAs (miRNAs). Required for miRNA-dependent translational repression of complementary mRNAs by argonaute family proteins. As scaffoldng protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes.

Subunit / interactions. Interacts with one or more of the argonaute family proteins AGO1, AGO2, AGO3 and AGO4. Interacts with PABPC1 and EIF4G1. Interacts with CNOT1; the interaction is direct and mediates the association with the CCR4-NOT complex. Interacts with PAN3; the interaction mediates the association with the PAN complex.

Domain organisation. The silencing domain, also known as C-terminal effector domain (CED), can act in autonomous repression, including both translational inhibition and mRNA degradation.

Similarity. Belongs to the GW182 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9HCJ0-3	3	yes
Q9HCJ0-1	1
Q9HCJ0-2	2
Q9HCJ0-4	4

RefSeq proteins (7): NP_001136112, NP_001382437, NP_001382438, NP_001382439, NP_001382440, NP_001382441, NP_061869 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR015940	UBA	Domain
IPR019486	Argonaute_hook_dom	Domain
IPR026805	GW182_M_dom	Domain
IPR032226	TNRC6_PABC-bd	Domain
IPR034927	TNRC6C_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR041917	TNR6C_UBA	Domain
IPR052068	GW182_domain	Family

Pfam: PF00076, PF00627, PF10427, PF12938, PF16608

UniProt features (81 total): compositionally biased region 31, region of interest 16, mutagenesis site 15, modified residue 5, splice variant 3, helix 3, domain 2, sequence conflict 2, chain 1, coiled-coil region 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2X04	X-RAY DIFFRACTION	1.49
3KTP	X-RAY DIFFRACTION	1.5
7RUQ	X-RAY DIFFRACTION	1.79
2DKL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCJ0-F1	40.94	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 (5): 523, 675, 924, 987, 1218

Mutagenesis-validated functional residues (15):

Position	Phenotype
1501–1507	abolishes association with ccr4-not complex.
1595–1596	abolishes interaction with pabpc1, impairs interaction with pan2, no effect on interaction with ccr4-not complex, reduce
1602–1603	abolishes interaction with pabpc1, impairs interaction with pan2, no effect on interaction with ccr4-not complex, reduce
1691	abolishes translational repression when tethered to a target mrna, abolishes association with the ccr4-not complex; when
1733	abolishes translational repression when tethered to a target mrna, abolishes association with the ccr4-not complex; when
1740	abolishes translational repression when tethered to a target mrna, abolishes association with the ccr4-not complex; when
1750	abolishes translational repression when tethered to a target mrna, abolishes association with the ccr4-not complex; when
1761	abolishes translational repression when tethered to a target mrna, abolishes association with the ccr4-not complex; when
1783	strongly reduced ability to repress translation of target mrnas.
1789	weakly reduced ability to repress translation of target mrnas.
1802	strongly reduced ability to repress translation of target mrnas.
1851	abolishes translational repression when tethered to a target mrna, abolishes association with the ccr4-not complex; when
1893–1895	impairs interaction with the ccr4-not complex, no effect on interaction with pabpc1; when associated with 1658-a-a-1906.
1894	abolishes translational repression when tethered to a target mrna, abolishes association with the ccr4-not complex; when
1904–1906	impairs interaction with the ccr4-not complex, no effect on interaction with pabpc1; when associated with 1647-a-a-1895.

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-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-9725371	Nuclear events stimulated by ALK signaling in cancer
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: 287 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, REACTOME_SIGNALING_BY_NOTCH, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, PEREZ_TP63_TARGETS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_NUCLEAR_TRANSCRIBED_MRNA_POLY_A_TAIL_SHORTENING, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS

GO Biological Process (6): 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), regulatory ncRNA-mediated gene silencing (GO:0031047)

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
Signaling by ALK fusions and activated point mutants	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
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
negative regulation of gene expression	1
nucleic acid binding	1
cytoplasmic ribonucleoprotein granule	1
nuclear lumen	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNRC6C	AGO2	Q9UKV8	853
TNRC6C	AGO1	Q9UL18	805
TNRC6C	PABPC1	P11940	753
TNRC6C	CNOT9	Q92600	730
TNRC6C	AGO3	Q9H9G7	614
TNRC6C	AGO4	Q9HCK5	614
TNRC6C	DDX6	P26196	539
TNRC6C	XRN1	Q8IZH2	530
TNRC6C	CNOT7	Q9UIV1	470
TNRC6C	CNOT1	A5YKK6	466
TNRC6C	CPSF7	Q8N684	443
TNRC6C	CPSF2	Q9P2I0	439
TNRC6C	CPSF6	Q16630	425
TNRC6C	HNRNPD	P07029	425
TNRC6C	IGF2BP3	O00425	424

IntAct

90 interactions, top by confidence:

A	B	Type	Score
TNRC6C	PABPC1	psi-mi:“MI:0407”(direct interaction)	0.910
TNRC6C	PABPC1	psi-mi:“MI:0915”(physical association)	0.910
TNRC6C	PABPC1	psi-mi:“MI:0914”(association)	0.910
PABPC1	TNRC6C	psi-mi:“MI:0915”(physical association)	0.910
PABPC1	TNRC6C	psi-mi:“MI:0407”(direct interaction)	0.910
AGO1	TNRC6A	psi-mi:“MI:0914”(association)	0.900
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
PPM1K	DBT	psi-mi:“MI:0914”(association)	0.790
AGO2	TNRC6C	psi-mi:“MI:0915”(physical association)	0.780
AGO2	TNRC6C	psi-mi:“MI:0403”(colocalization)	0.780
RACK1	RIOK3	psi-mi:“MI:0914”(association)	0.640
GATC	GATB	psi-mi:“MI:0914”(association)	0.640
TNRC6C	CNOT1	psi-mi:“MI:0914”(association)	0.620
TNRC6C	CNOT1	psi-mi:“MI:0915”(physical association)	0.620
CNOT2	TNRC6C	psi-mi:“MI:0915”(physical association)	0.620

BioGRID (215): PABPC1 (Affinity Capture-MS), PABPC4 (Affinity Capture-MS), CNOT1 (Affinity Capture-MS), CNOT10 (Affinity Capture-MS), CNOT3 (Affinity Capture-MS), CNOT8 (Affinity Capture-MS), PABPC1 (Affinity Capture-Western), CNOT1 (Affinity Capture-Western), CNOT8 (Affinity Capture-Western), CNOT3 (Affinity Capture-Western), CNOT6 (Affinity Capture-Western), PAN2 (Affinity Capture-Western), PAN3 (Affinity Capture-Western), PABPC1 (Affinity Capture-Western), TNRC6C (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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 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
Deadenylation of mRNA	11	81.9×	6e-17
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	8	70.4×	1e-11
Regulation of RUNX1 Expression and Activity	5	56.9×	5e-07
M-decay: degradation of maternal mRNAs by maternally stored factors	10	55.3×	2e-13
Regulation of MITF-M-dependent genes involved in apoptosis	5	53.8×	6e-07
TGFBR3 expression	5	38.7×	3e-06
Regulation of MECP2 expression and activity	5	31.2×	9e-06
Transcriptional Regulation by MECP2	5	26.9×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA poly(A) tail shortening	10	104.2×	4e-16
pre-miRNA processing	5	73.0×	6e-07
regulatory ncRNA-mediated gene silencing	7	61.3×	3e-09
miRNA-mediated gene silencing by inhibition of translation	5	57.6×	2e-06
regulation of translation	6	17.1×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	263
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3702 predictions. Top by Δscore:

Variant	Effect	Δscore
17:78004234:G:GT	donor_gain	1.0000
17:78004252:G:GT	donor_gain	1.0000
17:78004253:A:T	donor_gain	1.0000
17:78048843:A:AG	acceptor_gain	1.0000
17:78048844:G:GA	acceptor_gain	1.0000
17:78064707:T:A	acceptor_gain	1.0000
17:78064708:G:A	acceptor_gain	1.0000
17:78064720:A:AG	acceptor_gain	1.0000
17:78064721:G:GG	acceptor_gain	1.0000
17:78064934:CCAGG:C	donor_loss	1.0000
17:78064935:CAGGT:C	donor_loss	1.0000
17:78064937:GGTA:G	donor_loss	1.0000
17:78064938:G:C	donor_loss	1.0000
17:78064939:T:G	donor_loss	1.0000
17:78067752:TCTA:T	acceptor_loss	1.0000
17:78067753:CTA:C	acceptor_loss	1.0000
17:78067755:A:AG	acceptor_gain	1.0000
17:78067756:G:A	acceptor_loss	1.0000
17:78067756:G:GT	acceptor_gain	1.0000
17:78067756:GC:G	acceptor_gain	1.0000
17:78067756:GCT:G	acceptor_gain	1.0000
17:78067756:GCTT:G	acceptor_gain	1.0000
17:78067756:GCTTC:G	acceptor_gain	1.0000
17:78067920:AAAG:A	donor_gain	1.0000
17:78067921:AAG:A	donor_gain	1.0000
17:78067922:AG:A	donor_gain	1.0000
17:78067923:GG:G	donor_gain	1.0000
17:78067924:G:GG	donor_gain	1.0000
17:78071073:A:AG	acceptor_gain	1.0000
17:78071073:ACTTT:A	acceptor_gain	1.0000

AlphaMissense

12702 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:78051190:T:A	W710R	1.000
17:78051190:T:C	W710R	1.000
17:78093115:T:A	W1385R	1.000
17:78093115:T:C	W1385R	1.000
17:78093622:T:C	F1389L	1.000
17:78093623:T:C	F1389S	1.000
17:78093623:T:G	F1389C	1.000
17:78093624:C:A	F1389L	1.000
17:78093624:C:G	F1389L	1.000
17:78093640:T:A	W1395R	1.000
17:78093640:T:C	W1395R	1.000
17:78093641:G:C	W1395S	1.000
17:78093642:G:C	W1395C	1.000
17:78093642:G:T	W1395C	1.000
17:78102519:T:C	L1516P	1.000
17:78102525:T:A	L1518H	1.000
17:78102525:T:C	L1518P	1.000
17:78102534:T:A	L1521H	1.000
17:78102534:T:C	L1521P	1.000
17:78103415:T:A	I1525N	1.000
17:78103415:T:G	I1525S	1.000
17:78103418:A:T	D1526V	1.000
17:78103421:G:A	G1527D	1.000
17:78103430:T:A	L1530Q	1.000
17:78103430:T:C	L1530P	1.000
17:78103433:G:C	R1531P	1.000
17:78103439:T:C	L1533S	1.000
17:78103441:T:C	C1534R	1.000
17:78103442:G:A	C1534Y	1.000
17:78103443:T:G	C1534W	1.000

dbSNP variants (sampled 300 via entrez): RS1000023578 (17:77985844 G>C), RS1000026329 (17:78107351 A>C,G), RS1000049646 (17:78033869 T>A), RS1000053833 (17:77996331 G>A), RS1000136001 (17:78101870 G>A), RS1000138123 (17:78003033 G>A), RS1000151454 (17:77964066 A>C), RS1000159381 (17:78026107 A>G), RS1000174154 (17:78105080 C>T), RS1000187381 (17:78066212 CAG>C), RS1000210251 (17:78062473 A>G), RS1000219433 (17:78021215 T>G), RS1000222129 (17:77962561 C>T), RS1000223264 (17:77985717 T>A), RS1000256838 (17:78068921 A>C,T)

Disease associations

OMIM: gene MIM:610741 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001859_36	Thiazide-induced adverse metabolic effects in hypertensive patients	3.000000e-06
GCST005557_3	Serum uric acid levels	1.000000e-06
GCST006616_2	Uterine fibroid number (single vs multiple)	6.000000e-07
GCST007449_4	Normal facial asymmetry (angle of deformation score)	5.000000e-06
GCST010002_132	Refractive error	4.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004761	uric acid measurement
EFO:0009410	uterine fibroid measurement
EFO:0009751	facial asymmetry measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
methylmercuric chloride	decreases expression, increases expression	2
Acetaminophen	increases expression	2
Benzo(a)pyrene	decreases expression, affects methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
pinosylvin	decreases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Catechin	affects cotreatment, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	increases expression	1
Smoke	decreases expression, increases abundance	1
Tetrachlorodibenzodioxin	affects expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders