TGS1

Summary

TGS1 (trimethylguanosine synthase 1, HGNC:17843) is a protein-coding gene on chromosome 8q12.1, encoding Trimethylguanosine synthase (Q96RS0). Catalyzes the 2 serial methylation steps for the conversion of the 7-monomethylguanosine (m(7)G) caps of snRNAs and snoRNAs to a 2,2,7-trimethylguanosine (m(2,2,7)G) cap structure. It is a selective cancer dependency (DepMap: 74.7% of cell lines).

Enables RNA cap trimethylguanosine synthase activity. Involved in 7-methylguanosine cap hypermethylation. Located in cytosol and nucleus.

Source: NCBI Gene 96764 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 142 total
• Cancer dependency (DepMap): dependent in 74.7% of screened cell lines
• MANE Select transcript: NM_024831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17843
Approved symbol	TGS1
Name	trimethylguanosine synthase 1
Location	8q12.1
Locus type	gene with protein product
Status	Approved
Aliases	PIMT
Ensembl gene	ENSG00000137574
Ensembl biotype	protein_coding
OMIM	606461
Entrez	96764

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000260129, ENST00000519494, ENST00000523948, ENST00000872461, ENST00000938742, ENST00000938743

RefSeq mRNA: 3 — MANE Select: NM_024831 NM_001317902, NM_001363184, NM_024831

CCDS: CCDS34894

Canonical transcript exons

ENST00000260129 — 13 exons

Exon	Start	End
ENSE00000980361	55782748	55782812
ENSE00001310628	55773446	55773719
ENSE00001504720	55813040	55813118
ENSE00001504721	55810881	55811097
ENSE00002124685	55824581	55826445
ENSE00003491679	55792698	55792784
ENSE00003581374	55785719	55785891
ENSE00003598569	55795978	55796152
ENSE00003619172	55798914	55799220
ENSE00003651743	55802457	55802606
ENSE00003668049	55790182	55790299
ENSE00003684412	55804893	55805036
ENSE00003690032	55786238	55787060

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 97.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.4695 / max 216.9864, expressed in 1802 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88897	13.7723	1780
88898	6.4999	1650
88899	0.1973	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	97.02	gold quality
oocyte	CL:0000023	96.29	gold quality
secondary oocyte	CL:0000655	93.78	gold quality
tendon	UBERON:0000043	92.20	gold quality
calcaneal tendon	UBERON:0003701	90.14	gold quality
nipple	UBERON:0002030	89.76	gold quality
cauda epididymis	UBERON:0004360	89.60	gold quality
pylorus	UBERON:0001166	89.27	gold quality
medial globus pallidus	UBERON:0002477	89.04	gold quality
renal medulla	UBERON:0000362	88.66	gold quality
corpus epididymis	UBERON:0004359	88.35	gold quality
mammary duct	UBERON:0001765	86.89	gold quality
caput epididymis	UBERON:0004358	86.81	gold quality
ventricular zone	UBERON:0003053	86.41	gold quality
gingival epithelium	UBERON:0001949	86.35	gold quality
lower lobe of lung	UBERON:0008949	86.34	gold quality
palpebral conjunctiva	UBERON:0001812	86.30	gold quality
cardia of stomach	UBERON:0001162	86.13	gold quality
gingiva	UBERON:0001828	86.11	gold quality
parietal pleura	UBERON:0002400	86.11	gold quality
germinal epithelium of ovary	UBERON:0001304	86.08	gold quality
globus pallidus	UBERON:0001875	85.86	gold quality
urethra	UBERON:0000057	85.61	gold quality
epithelium of mammary gland	UBERON:0003244	85.30	gold quality
tonsil	UBERON:0002372	85.22	gold quality
pleura	UBERON:0000977	84.98	gold quality
visceral pleura	UBERON:0002401	83.96	gold quality
ganglionic eminence	UBERON:0004023	83.93	gold quality
amniotic fluid	UBERON:0000173	83.81	gold quality
buccal mucosa cell	CL:0002336	83.76	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.66
E-MTAB-3929	no	274.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

87 targeting TGS1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 74.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• Interaction of PIMT with transcriptional coactivators CBP, p300, and PBP differential role in transcriptional regulation. (PMID:11912212)
• isoforms of the PIMT/Tgs1 protein with an RNA methyltransferase domain function both in the nucleus and in the cytoplasm (PMID:12943661)
• proteasome maturation constitutes a mechanism regulating Tgs1 function by generating Tgs1 species with different substrate specificities, subcellular localizations, and functions. (PMID:18039666)
• These results highlight that PIMT expression is regulated by ROS and could primarily act as an antioxidant enzyme. (PMID:18407833)
• present a biochemical characterization of the human Tgs1 guanine-N2 methyltransferase reaction and identify individual amino acids required for methyltransferase activity in vitro and in vivo (PMID:18775984)
• m(7)GpppA binds via its adenosine moiety to the structurally conserved adenosylmethionine-binding pocket. The m(7) guanosine is unbound. The crystallized TGS1 fragment is catalytically inactive, but a fragment that is 17 AAs longer exhibits activity. (PMID:19307714)
• The crystal structure of the substrate bound methyltransferase domain as well as mutagenesis studies provide insight into the catalytic mechanism of TGS1. (PMID:19386620)
• The structure-function data highlight a strictly essential pi-cation interaction between Trp766 and the m(7)G base and a network of important enzymic contacts to the cap triphosphate via Lys646, Tyr771, Arg807, and Lys836. (PMID:20360394)
• The protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT) is an enzyme that recognizes and repairs the abnormal L-isoaspartyl residues in proteins. (PMID:21204776)
• PIMT was identified as a key player responsible for glycated low density lipoproteins induced vascular endothelial cell apoptosis. (PMID:23922881)
• Self-association of Tgs1p and its catalytic activity were prerequisite to bypass the requirement for its accessory factor Swm2p for efficient pre-rRNA processing and snRNA trimethylation. (PMID:26074133)
• Data highlight the importance of the catalytic activity of PIMT to mediate VEGF effects during endothelial cell migration and tube formation in angiogenesis. (PMID:26738492)
• Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation. (PMID:32023455)
• TGS1 impacts snRNA 3’-end processing, ameliorates survival motor neuron-dependent neurological phenotypes in vivo and prevents neurodegeneration. (PMID:35947650)
• TGS1/PIMT knockdown reduces lipid accumulation in adipocytes, limits body weight gain and promotes insulin sensitivity in mice. (PMID:37751782)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgs1	ENSDARG00000107511
mus_musculus	Tgs1	ENSMUSG00000028233
rattus_norvegicus	Tgs1	ENSRNOG00000008156
drosophila_melanogaster	Tgs1	FBGN0266195
caenorhabditis_elegans	tgs-1	WBGENE00011631

Protein

Protein identifiers

Trimethylguanosine synthase — Q96RS0 (reviewed: Q96RS0)

Alternative names: CLL-associated antigen KW-2, Cap-specific guanine-N(2) methyltransferase, Hepatocellular carcinoma-associated antigen 137, Nuclear receptor coactivator 6-interacting protein, PRIP-interacting protein with methyltransferase motif

All UniProt accessions (2): E5RJW7, Q96RS0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the 2 serial methylation steps for the conversion of the 7-monomethylguanosine (m(7)G) caps of snRNAs and snoRNAs to a 2,2,7-trimethylguanosine (m(2,2,7)G) cap structure. The enzyme is specific for guanine, and N7 methylation must precede N2 methylation. Hypermethylation of the m7G cap of U snRNAs leads to their concentration in nuclear foci, their colocalization with coilin and the formation of canonical Cajal bodies (CBs). Plays a role in transcriptional regulation.

Subunit / interactions. May form homooligomers. Interacts with CREBBP/CBP, EED/WAIT1, EP300/P300, NCOA6/PRIP, PPARBP/PBP and SMN.

Subcellular location. Cytoplasm. Nucleus. Cajal body. Nucleolus.

Tissue specificity. Ubiquitously expressed. High expression in heart, skeletal muscle, kidney, liver and placenta.

Similarity. Belongs to the methyltransferase superfamily. Trimethylguanosine synthase family.

RefSeq proteins (3): NP_001304831, NP_001350113, NP_079107* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019012	RNA_cap_Gua-N2-MeTrfase	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF09445

Catalyzed reactions (Rhea), 4 shown:

• a 5’-end (N(7)-methyl 5’-triphosphoguanosine)-ribonucleoside in snRNA + S-adenosyl-L-methionine = a 5’-end (N(2),N(7)-dimethyl 5’-triphosphoguanosine)-ribonucleoside in snRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:78471)
• a 5’-end (N(7)-methyl 5’-triphosphoguanosine)-ribonucleoside in snoRNA + S-adenosyl-L-methionine = a 5’-end (N(2),N(7)-dimethyl 5’-triphosphoguanosine)-ribonucleoside in snoRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:78475)
• a 5’-end (N(2),N(7)-dimethyl 5’-triphosphoguanosine)-ribonucleoside in snRNA + S-adenosyl-L-methionine = a 5’-end (N(2),N(2),N(7)-trimethyl 5’-triphosphoguanosine)-ribonucleoside in snRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:78479)
• a 5’-end (N(2),N(7)-dimethyl 5’-triphosphoguanosine)-ribonucleoside in snoRNA + S-adenosyl-L-methionine = a 5’-end (N(2),N(2),N(7)-trimethyl 5’-triphosphoguanosine)-ribonucleoside in snoRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:78507)

UniProt features (74 total): helix 16, modified residue 12, mutagenesis site 10, strand 9, sequence variant 7, compositionally biased region 6, region of interest 5, sequence conflict 5, binding site 2, chain 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3GDH	X-RAY DIFFRACTION	2
3EGI	X-RAY DIFFRACTION	2.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RS0-F1	60.56	0.22

Functional residue map

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

Ligand- & substrate-binding residues (2): 719; 766

Post-translational modifications (12): 55, 60, 85, 89, 96, 141, 146, 154, 189, 412, 438, 578

Mutagenesis-validated functional residues (10):

Position	Phenotype
655	loss of catalytic activity.
673	decreases catalytic activity to 13 percent of wild type.
696	loss of catalytic activity.
704	decreases catalytic activity to 5 percent of wild type.
719	loss of catalytic activity.
731	decreases catalytic activity to 4 percent of wild type.
763	decreases catalytic activity to 26 percent of wild type.
766	loss of catalytic activity.
807	decreases catalytic activity to 6 percent of wild type.
808	decreases catalytic activity to 11 percent of wild type.

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-1368108	BMAL1:CLOCK,NPAS2 activates circadian expression
R-HSA-191859	snRNP Assembly
R-HSA-1989781	PPARA activates gene expression
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-2426168	Activation of gene expression by SREBF (SREBP)
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9707616	Heme signaling
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9933387	RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression
R-HSA-1266738	Developmental Biology
R-HSA-1368082
R-HSA-1430728	Metabolism
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-194441	Metabolism of non-coding RNA
R-HSA-2262752	Cellular responses to stress
R-HSA-400253
R-HSA-556833	Metabolism of lipids
R-HSA-8953854	Metabolism of RNA
R-HSA-8953897	Cellular responses to stimuli
R-HSA-8957322	Metabolism of steroids
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 161 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_RNA_METHYLATION, MARTINEZ_RB1_TARGETS_UP, ONKEN_UVEAL_MELANOMA_UP, GOBP_RNA_MODIFICATION, WANG_LMO4_TARGETS_DN, GOBP_RNA_CAPPING, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_METHYLATION, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, AP2_Q6_01

GO Biological Process (5): spliceosomal snRNP assembly (GO:0000387), ribonucleoprotein complex biogenesis (GO:0022613), 7-methylguanosine cap hypermethylation (GO:0036261), RNA methylation (GO:0001510), methylation (GO:0032259)

GO Molecular Function (5): RNA methyltransferase activity (GO:0008173), RNA cap trimethylguanosine synthase activity (GO:0071164), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), Cajal body (GO:0015030), small nuclear ribonucleoprotein complex (GO:0030532)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Circadian clock	3
Metabolism of non-coding RNA	1
Regulation of lipid metabolism by PPARalpha	1
Mitochondrial biogenesis	1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1
Adipogenesis	1
Metabolism of lipids	1
Cellular response to chemical stress	1
Cellular responses to stress	1
Organelle biogenesis and maintenance	1
Metabolism of steroids	1
Metabolism of RNA	1
Cellular responses to stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nuclear lumen	2
mRNA splicing, via spliceosome	1
protein-RNA complex assembly	1
cellular component biogenesis	1
RNA methylation	1
RNA capping	1
RNA modification	1
macromolecule methylation	1
metabolic process	1
methyltransferase activity	1
catalytic activity, acting on RNA	1
RNA methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
7-methylguanosine cap hypermethylation	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
Sm-like protein family complex	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1

Protein interactions and networks

STRING

1202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGS1	NCOA6	Q14686	946
TGS1	EP300	Q09472	586
TGS1	PHAX	Q9H814	565
TGS1	RNGTT	O60942	494
TGS1	GEMIN5	Q8TEQ6	494
TGS1	PPARG	P37231	490
TGS1	BUD13	Q9BRD0	489
TGS1	GEMIN2	O14893	485
TGS1	MED1	Q15648	479
TGS1	COIL	P38432	471
TGS1	MEPCE	Q7L2J0	460
TGS1	SNRPB	P14678	434
TGS1	ORC3	Q9UBD5	432
TGS1	HELZ2	Q9BYK8	415
TGS1	SNRPD3	P43331	410

IntAct

86 interactions, top by confidence:

A	B	Type	Score
SNRPF	GEMIN2	psi-mi:“MI:0914”(association)	0.910
LARP7	CCNT1	psi-mi:“MI:0914”(association)	0.850
FBL	NOP56	psi-mi:“MI:0914”(association)	0.800
SNRPE	GEMIN2	psi-mi:“MI:0914”(association)	0.770
FBL	TGS1	psi-mi:“MI:0915”(physical association)	0.740
SNRPD2	GEMIN2	psi-mi:“MI:0914”(association)	0.710
SNRPG	GEMIN2	psi-mi:“MI:0914”(association)	0.710
SNRPB	PRMT5	psi-mi:“MI:0914”(association)	0.670
TGS1	NOP58	psi-mi:“MI:0407”(direct interaction)	0.660
TGS1	NOP58	psi-mi:“MI:0915”(physical association)	0.660
SNRPA1	HTATSF1	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
SNRPA1	U2SURP	psi-mi:“MI:0914”(association)	0.640
SNRPB	SART1	psi-mi:“MI:0914”(association)	0.640
ZNF76	TGS1	psi-mi:“MI:0915”(physical association)	0.560
NOXA1	TGS1	psi-mi:“MI:0915”(physical association)	0.560
SNRPE	PRMT5	psi-mi:“MI:0914”(association)	0.530
SNRPN	PRMT5	psi-mi:“MI:0914”(association)	0.530
FAM177A1	SLC27A2	psi-mi:“MI:0914”(association)	0.530
FBL	ZNF316	psi-mi:“MI:0914”(association)	0.530
SNRPE	SNRPGP15	psi-mi:“MI:0914”(association)	0.530
SNRPF	SNRPGP15	psi-mi:“MI:0914”(association)	0.530
TGS1	SNRNP70	psi-mi:“MI:0914”(association)	0.530

BioGRID (115): TGS1 (Affinity Capture-MS), TGS1 (Affinity Capture-MS), TGS1 (Affinity Capture-MS), TGS1 (Affinity Capture-MS), SEPT7 (Affinity Capture-MS), CRY1 (Affinity Capture-MS), ERCC5 (Affinity Capture-MS), MYBPH (Affinity Capture-MS), SEPT2 (Affinity Capture-MS), SORBS1 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), DNAJB4 (Affinity Capture-MS), ZZEF1 (Affinity Capture-MS), SCRIB (Affinity Capture-MS)

ESM2 similar proteins: A0A0A6YYL3, A0JP26, A2A2Z9, A2RUR9, A6NC57, A6NI47, A6QR20, A8MYB1, A9JSR5, A9ZSY0, B2RU33, B7ZQJ9, F1M5M3, H3BUK9, O15050, P51954, P98182, Q19UN5, Q4UJ75, Q501X2, Q5CZ79, Q5DW34, Q5SQ80, Q5TYW2, Q5VUR7, Q66HB6, Q6NSI1, Q6S545, Q6S5H5, Q6S8J7, Q71S21, Q7TPV2, Q7TSC3, Q7ZT11, Q80X59, Q811D2, Q86Y13, Q86YR6, Q8IVF6, Q8IYA2

Diamond homologs: A0KNJ1, A3M6R7, A3MWC5, A4FWV6, A5D3Y3, A5IN97, A5UD93, A5UIB7, A5WFX2, A6UPM1, A6VGG1, A7MXI3, A9AA91, B0V7H8, B0VLL0, B1L841, B1LGM4, B4S130, B4SUN8, B5FC65, B5FIW1, B7H0I7, B7IC17, B7LHW6, B7VM52, B9K9N3, C3MJI5, C3MTW8, C3N0H8, C3N8G6, C3NJQ5, C4KJM8, C4LAF1, C6DY35, O13648, O26249, O86951, O87694, P21921, P60094

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Metabolism of non-coding RNA	7	76.6×	8e-11
mRNA Splicing	17	32.2×	1e-19
SARS-CoV-2 modulates host translation machinery	8	30.9×	5e-09
snRNP Assembly	8	29.2×	7e-09
Processing of Capped Intron-Containing Pre-mRNA	17	24.1×	1e-17
mRNA Polyadenylation	15	22.7×	3e-15
mRNA Splicing - Minor Pathway	5	19.3×	1e-04
RNA Polymerase II Transcription Termination	5	18.9×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
spliceosomal snRNP assembly	11	88.8×	5e-17
U2-type prespliceosome assembly	8	69.3×	2e-11
spliceosomal complex assembly	6	50.1×	1e-07
mRNA splicing, via spliceosome	16	20.4×	9e-15
ribosomal small subunit biogenesis	6	19.0×	4e-05
RNA splicing	11	13.5×	4e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	9
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

2328 predictions. Top by Δscore:

Variant	Effect	Δscore
8:55782720:A:AG	acceptor_gain	1.0000
8:55787059:GG:G	donor_gain	1.0000
8:55787060:GG:G	donor_gain	1.0000
8:55790177:TTTA:T	acceptor_loss	1.0000
8:55790178:TTAG:T	acceptor_loss	1.0000
8:55790180:A:AG	acceptor_gain	1.0000
8:55790181:G:A	acceptor_loss	1.0000
8:55790181:G:GG	acceptor_gain	1.0000
8:55790296:GGAG:G	donor_gain	1.0000
8:55790297:GAG:G	donor_gain	1.0000
8:55790297:GAGG:G	donor_gain	1.0000
8:55790300:G:GA	donor_loss	1.0000
8:55790300:G:GG	donor_gain	1.0000
8:55790301:TAAG:T	donor_loss	1.0000
8:55792767:G:GG	donor_gain	1.0000
8:55792778:G:GT	donor_gain	1.0000
8:55792785:G:GG	donor_gain	1.0000
8:55796148:GTAAG:G	donor_gain	1.0000
8:55802446:T:G	acceptor_gain	1.0000
8:55802450:A:AG	acceptor_gain	1.0000
8:55802451:T:G	acceptor_gain	1.0000
8:55802453:TTAGC:T	acceptor_gain	1.0000
8:55802454:TAGCT:T	acceptor_gain	1.0000
8:55802455:A:AG	acceptor_gain	1.0000
8:55802455:AGCT:A	acceptor_gain	1.0000
8:55802455:AGCTG:A	acceptor_gain	1.0000
8:55802456:G:GG	acceptor_gain	1.0000
8:55802456:GC:G	acceptor_gain	1.0000
8:55802456:GCT:G	acceptor_gain	1.0000
8:55802456:GCTG:G	acceptor_gain	1.0000

AlphaMissense

5718 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:55804898:T:A	W669R	0.999
8:55804898:T:C	W669R	0.999
8:55811033:T:A	W766R	0.999
8:55811033:T:C	W766R	0.999
8:55802568:T:C	L654P	0.998
8:55804901:T:C	F670L	0.998
8:55804903:T:A	F670L	0.998
8:55804903:T:G	F670L	0.998
8:55810930:T:A	N731K	0.998
8:55810930:T:G	N731K	0.998
8:55802559:G:C	R651T	0.997
8:55802559:G:T	R651M	0.997
8:55802560:G:C	R651S	0.997
8:55802560:G:T	R651S	0.997
8:55802570:T:C	F655L	0.997
8:55802572:C:A	F655L	0.997
8:55802572:C:G	F655L	0.997
8:55804895:G:C	G668R	0.997
8:55804926:C:A	A678D	0.997
8:55804938:C:A	A682D	0.997
8:55804985:T:C	F698L	0.997
8:55804987:C:A	F698L	0.997
8:55804987:C:G	F698L	0.997
8:55810931:G:C	A732P	0.997
8:55811024:A:C	S763R	0.997
8:55811026:C:A	S763R	0.997
8:55811026:C:G	S763R	0.997
8:55811035:G:C	W766C	0.997
8:55811035:G:T	W766C	0.997
8:55802571:T:C	F655S	0.996

dbSNP variants (sampled 300 via entrez): RS1000022639 (8:55778109 T>A), RS1000122013 (8:55779165 A>G,T), RS1000156856 (8:55774536 T>A), RS1000189121 (8:55790989 A>G,T), RS1000192898 (8:55780593 A>G), RS1000219769 (8:55821878 A>T), RS1000237512 (8:55796977 TAA>T), RS1000250286 (8:55796616 A>T), RS1000250730 (8:55822111 C>T), RS1000264672 (8:55779009 T>C), RS1000348140 (8:55793645 G>A,T), RS1000369140 (8:55824252 T>A), RS1000377038 (8:55791427 A>G), RS1000381267 (8:55775621 A>G), RS1000412051 (8:55813194 C>T)

Disease associations

OMIM: gene MIM:606461 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000175_46	Height	7.000000e-08
GCST002458_1	Serum thyroid-stimulating hormone levels	2.000000e-10
GCST003875_3	Gut microbiota (bacterial taxa)	6.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	decreases expression, increases abundance	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
Temozolomide	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, decreases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	decreases expression	1
Colforsin	increases expression	1
Indomethacin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Tretinoin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

Clinical trials (associated diseases)

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