THUMPD2

Summary

THUMPD2 (THUMP domain 2 tRNA and snRNA guanosine methyltransferase, HGNC:14890) is a protein-coding gene on chromosome 2p22.1, encoding U6 snRNA (guanine-N(2))-methyltransferase THUMPD2 (Q9BTF0). Catalytic subunit of the THUMPD2-TRM112 methyltransferase complex, that specifically mediates the S-adenosyl-L-methionine-dependent N(2)-methylation of guanosine nucleotides, most probably at position 72 (m2G72), in the U6snRNA of the major spliceosome.

Enables snRNA methyltransferase activity. Involved in regulation of alternative mRNA splicing, via spliceosome. Part of tRNA methyltransferase complex. Is active in nucleus.

Source: NCBI Gene 80745 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 114 total
• MANE Select transcript: NM_025264

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14890
Approved symbol	THUMPD2
Name	THUMP domain 2 tRNA and snRNA guanosine methyltransferase
Location	2p22.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC2454
Ensembl gene	ENSG00000138050
Ensembl biotype	protein_coding
OMIM	611751
Entrez	80745

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000378727, ENST00000403537, ENST00000460072, ENST00000505747, ENST00000510781, ENST00000527689, ENST00000530095, ENST00000530522, ENST00000531687, ENST00000933808, ENST00000933809, ENST00000933810, ENST00000933811, ENST00000933812, ENST00000933813, ENST00000933814, ENST00000953485

RefSeq mRNA: 11 — MANE Select: NM_025264 NM_001321468, NM_001321469, NM_001321470, NM_001321474, NM_001321475, NM_001321477, NM_001321478, NM_001321479, NM_001321480, NM_001321481, NM_025264

CCDS: CCDS1805

Canonical transcript exons

ENST00000505747 — 10 exons

Exon	Start	End
ENSE00001620073	39736061	39737059
ENSE00003467368	39769710	39770119
ENSE00003472914	39744370	39744478
ENSE00003528582	39761331	39761418
ENSE00003547695	39771505	39771640
ENSE00003596318	39768424	39768501
ENSE00003605092	39766057	39766109
ENSE00003629577	39755889	39755960
ENSE00003655678	39755295	39755409
ENSE00003841951	39779114	39779258

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 91.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.6218 / max 247.5100, expressed in 1768 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27935	13.3269	1764
27934	0.2949	137

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ascending aorta	UBERON:0001496	91.17	gold quality
thoracic aorta	UBERON:0001515	91.09	gold quality
descending thoracic aorta	UBERON:0002345	91.07	gold quality
calcaneal tendon	UBERON:0003701	90.44	gold quality
right coronary artery	UBERON:0001625	89.89	gold quality
cerebellar hemisphere	UBERON:0002245	89.49	gold quality
cerebellar cortex	UBERON:0002129	89.33	gold quality
left ovary	UBERON:0002119	88.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.99	gold quality
aorta	UBERON:0000947	88.96	gold quality
right ovary	UBERON:0002118	87.57	gold quality
popliteal artery	UBERON:0002250	87.53	gold quality
tibial artery	UBERON:0007610	87.52	gold quality
cerebellum	UBERON:0002037	87.39	gold quality
mucosa of stomach	UBERON:0001199	86.91	gold quality
ventricular zone	UBERON:0003053	86.91	gold quality
skin of abdomen	UBERON:0001416	86.59	gold quality
left coronary artery	UBERON:0001626	86.48	gold quality
body of uterus	UBERON:0009853	86.23	gold quality
skin of leg	UBERON:0001511	85.95	gold quality
ovary	UBERON:0000992	85.87	gold quality
endocervix	UBERON:0000458	85.58	gold quality
coronary artery	UBERON:0001621	85.48	gold quality
tibial nerve	UBERON:0001323	85.46	gold quality
minor salivary gland	UBERON:0001830	85.24	gold quality
left lobe of thyroid gland	UBERON:0001120	84.80	gold quality
adenohypophysis	UBERON:0002196	84.78	gold quality
ectocervix	UBERON:0012249	84.76	gold quality
adrenal tissue	UBERON:0018303	84.71	gold quality
body of pancreas	UBERON:0001150	84.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting THUMPD2, 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-3163	100.00	77.23	8605
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-7151-3P	99.04	69.72	2370

Literature-anchored findings (GeneRIF, showing 1)

• THUMPD2 catalyzes the N2-methylation of U6 snRNA of the spliceosome catalytic center and regulates pre-mRNA splicing and retinal degeneration. (PMID:38165050)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	thumpd2	ENSDARG00000093070
mus_musculus	Thumpd2	ENSMUSG00000024246
rattus_norvegicus	Thumpd2	ENSRNOG00000008291
caenorhabditis_elegans		WBGENE00010846

Paralogs (1): THUMPD3 (ENSG00000134077)

Protein

Protein identifiers

U6 snRNA (guanine-N(2))-methyltransferase THUMPD2 — Q9BTF0 (reviewed: Q9BTF0)

Alternative names: THUMP domain-containing protein 2

All UniProt accessions (2): Q9BTF0, H0YE26

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the THUMPD2-TRM112 methyltransferase complex, that specifically mediates the S-adenosyl-L-methionine-dependent N(2)-methylation of guanosine nucleotides, most probably at position 72 (m2G72), in the U6snRNA of the major spliceosome. This modification in the U6 snRNA affects the constitutive splicing efficiency of introns that have suboptimal splice sites and can impact final mRNA levels.

Subunit / interactions. Part of the heterodimeric THUMPD2-TRM112 methyltransferase complex; this complex forms an active tRNA methyltransferase, where TRMT112 acts as an activator of the catalytic subunit THUMPD2.

Subcellular location. Nucleus.

Tissue specificity. Expressed in a variety of tissues including brain, colon, gingiva, heart, kidney, liver, lung, placenta, small intestine, spleen and thymus.

Similarity. Belongs to the methyltransferase superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BTF0-1	1	yes
Q9BTF0-2	2

RefSeq proteins (11): NP_001308397, NP_001308398, NP_001308399, NP_001308403, NP_001308404, NP_001308406, NP_001308407, NP_001308408, NP_001308409, NP_001308410, NP_079540* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000241	RlmKL-like_Mtase	Domain
IPR004114	THUMP_dom	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF01170, PF02926

Catalyzed reactions (Rhea), 1 shown:

• guanosine in U6 snRNA + S-adenosyl-L-methionine = N(2)-methylguanosine in U6 snRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:83423)

UniProt features (4 total): splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BTF0-F1	74.60	0.55

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 131 (showing top): GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, GOBP_TRNA_METABOLIC_PROCESS, GOBP_RNA_METHYLATION, WEI_MYCN_TARGETS_WITH_E_BOX, ONKEN_UVEAL_MELANOMA_UP, GOBP_RNA_MODIFICATION, USF_01, GOBP_RNA_SPLICING, GOBP_TRNA_METHYLATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_REGULATION_OF_MRNA_SPLICING_VIA_SPLICEOSOME, USF_02, GOBP_METHYLATION, GOBP_TRNA_PROCESSING, GOBP_REGULATION_OF_RNA_SPLICING

GO Biological Process (4): regulation of alternative mRNA splicing, via spliceosome (GO:0000381), tRNA methylation (GO:0030488), RNA processing (GO:0006396), methylation (GO:0032259)

GO Molecular Function (6): RNA binding (GO:0003723), tRNA (guanine) methyltransferase activity (GO:0016423), U6 snRNA (guanine-N(2))-methyltransferase activity (GO:0160230), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (2): nucleus (GO:0005634), tRNA methyltransferase complex (GO:0043527)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
RNA methylation	1
tRNA modification	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
metabolic process	1
nucleic acid binding	1
tRNA methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
snRNA methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
methyltransferase complex	1

Protein interactions and networks

STRING

868 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THUMPD2	SOS1	Q07889	732
THUMPD2	TRMT11	Q7Z4G4	624
THUMPD2	TRMT1L	Q7Z2T5	539
THUMPD2	TRMT1	Q9NXH9	538
THUMPD2	BUD23	O43709	528
THUMPD2	FYTTD1	Q96QD9	523
THUMPD2	ZBTB8OS	Q8IWT0	496
THUMPD2	YRDC	Q86U90	483
THUMPD2	TRMT112	Q9UI30	475
THUMPD2	TRMT10B	Q6PF06	452
THUMPD2	ZBTB37	Q5TC79	449
THUMPD2	RGS1	Q08116	445
THUMPD2	PUS10	Q3MIT2	442
THUMPD2	TRMT2B	Q96GJ1	433
THUMPD2	FAM222B	Q8WU58	430

IntAct

16 interactions, top by confidence:

A	B	Type	Score
TRMT112	BUD23	psi-mi:“MI:0914”(association)	0.910
THUMPD2	WFS1	psi-mi:“MI:0915”(physical association)	0.560
THUMPD2	TRMT112	psi-mi:“MI:0915”(physical association)	0.540
THUMPD2	TRMT112	psi-mi:“MI:0403”(colocalization)	0.540
THUMPD2	SPDL1	psi-mi:“MI:0914”(association)	0.530
THUMPD2	NOP58	psi-mi:“MI:0915”(physical association)	0.400
HNRNPCL2	THUMPD2	psi-mi:“MI:0915”(physical association)	0.400
THUMPD2	RALY	psi-mi:“MI:0915”(physical association)	0.400
HSPB2	THUMPD2	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (19): THUMPD2 (Two-hybrid), SPDL1 (Affinity Capture-MS), LACRT (Affinity Capture-MS), THUMPD2 (Co-fractionation), THUMPD2 (Proximity Label-MS), RALY (Proximity Label-MS), NOP58 (Proximity Label-MS), LACRT (Affinity Capture-MS), SPDL1 (Affinity Capture-MS), THUMPD2 (Co-fractionation), DUS2 (Co-fractionation), SHOC2 (Co-fractionation), THUMPD2 (Cross-Linking-MS (XL-MS)), THUMPD2 (Affinity Capture-MS), THUMPD2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A1L3L1, A2RT67, A3KPW7, A4IIA7, A8C750, A8C752, D2HNY3, E1BGQ2, E1C3P4, Q08CL8, Q08DZ8, Q0IHB3, Q149N8, Q1RMU2, Q1RMZ1, Q3MJ13, Q3T1H6, Q5F3F2, Q5RED8, Q5VVJ2, Q5ZJ87, Q66J91, Q69Z66, Q6AYF5, Q6DE97, Q6GR37, Q6P1E7, Q6PNC0, Q6YHU6, Q7TPQ3, Q8BKW4, Q8BXK4, Q8IWR0, Q8IYF3, Q8IZE3, Q8K2I9, Q8NA31, Q8NEN0, Q8NFZ0, Q96EW2

Diamond homologs: A0A0D3MJQ5, B2IUM7, B5FE19, E1B8U2, O66128, Q18511, Q2SN12, Q3A209, Q5E5B4, Q6N3Y0, Q72IH5, Q8KZ94, Q8U248, Q9BTF0, Q9CZB3, A5W9K3, B0KJZ2, B1J5U4, O26820, O29011, O94636, P05409, Q03055, Q1I4C5, Q57880, Q58120, Q59047, Q6NS23, Q74CC6, Q87BR3, Q88DK7, Q96RS0, Q97WC7, Q9PAY7, Q9UY84, A0L8B5, P97770, Q2T9W2, Q9BV44, C3MJI5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
THUMPD2	“form complex”	“THUMPD2-TRM112 methyltransferase complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	93
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1304 predictions. Top by Δscore:

Variant	Effect	Δscore
2:39737058:CT:C	acceptor_gain	1.0000
2:39744365:CTTA:C	donor_loss	1.0000
2:39744366:TTA:T	donor_loss	1.0000
2:39744367:TACCT:T	donor_loss	1.0000
2:39744368:A:AC	donor_gain	1.0000
2:39744368:AC:A	donor_gain	1.0000
2:39744369:C:CT	donor_gain	1.0000
2:39744369:CC:C	donor_gain	1.0000
2:39744369:CCTTT:C	donor_gain	1.0000
2:39744477:TT:T	acceptor_gain	1.0000
2:39744479:C:CC	acceptor_gain	1.0000
2:39755871:CCAAA:C	donor_gain	1.0000
2:39755875:A:C	donor_gain	1.0000
2:39755887:A:AC	donor_gain	1.0000
2:39755888:C:CC	donor_gain	1.0000
2:39755888:CTGG:C	donor_gain	1.0000
2:39757247:CCCCA:C	donor_gain	1.0000
2:39761325:TCTTA:T	donor_loss	1.0000
2:39761326:CTTA:C	donor_loss	1.0000
2:39761328:TACCT:T	donor_loss	1.0000
2:39761329:A:AC	donor_gain	1.0000
2:39761330:C:CC	donor_gain	1.0000
2:39761330:C:CG	donor_loss	1.0000
2:39761415:AACC:A	acceptor_gain	1.0000
2:39761416:ACC:A	acceptor_gain	1.0000
2:39761417:CC:C	acceptor_gain	1.0000
2:39761417:CCC:C	acceptor_gain	1.0000
2:39761418:CC:C	acceptor_gain	1.0000
2:39761419:C:CC	acceptor_gain	1.0000
2:39761419:C:T	acceptor_gain	1.0000

AlphaMissense

3329 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:39768456:A:G	W240R	0.985
2:39768456:A:T	W240R	0.985
2:39771612:A:G	F52S	0.985
2:39769761:G:C	F207L	0.983
2:39769761:G:T	F207L	0.983
2:39769763:A:G	F207L	0.983
2:39779182:A:G	C20R	0.983
2:39771618:A:T	V50D	0.982
2:39779180:G:C	C20W	0.982
2:39744426:A:C	F377L	0.981
2:39744426:A:T	F377L	0.981
2:39744428:A:G	F377L	0.981
2:39755947:A:T	V302D	0.981
2:39766073:C:A	G263W	0.981
2:39771554:A:C	F71L	0.980
2:39771554:A:T	F71L	0.980
2:39771556:A:G	F71L	0.980
2:39761400:T:A	R274S	0.976
2:39761400:T:G	R274S	0.976
2:39769747:C:G	R212P	0.976
2:39766072:C:T	G263E	0.975
2:39771611:G:C	F52L	0.975
2:39771611:G:T	F52L	0.975
2:39771613:A:G	F52L	0.975
2:39766073:C:G	G263R	0.974
2:39766073:C:T	G263R	0.974
2:39769758:T:A	R208S	0.974
2:39769758:T:G	R208S	0.974
2:39769762:A:G	F207S	0.974
2:39770069:A:G	W105R	0.974

dbSNP variants (sampled 300 via entrez): RS1000007173 (2:39755167 G>A), RS1000011613 (2:39778648 C>A,T), RS1000116185 (2:39773738 T>C,G), RS1000126630 (2:39741522 A>C), RS1000134730 (2:39761155 T>C), RS1000232819 (2:39773464 T>G), RS1000269107 (2:39735704 T>C), RS1000270632 (2:39777491 T>A), RS1000308504 (2:39740444 C>T), RS1000371292 (2:39747303 G>A,T), RS1000476975 (2:39771873 G>A), RS1000526458 (2:39778255 T>A,C), RS1000585010 (2:39756572 G>A), RS1000635643 (2:39751001 T>C), RS1000680154 (2:39740171 CAT>C)

Disease associations

OMIM: gene MIM:611751 | 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
GCST000273_3	Personality dimensions	3.000000e-06
GCST008178_2	Early spontaneous preterm birth	3.000000e-06
GCST009391_1736	Metabolite levels	1.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004365	personality trait
EFO:0006917	spontaneous preterm birth
EFO:0010376	phosphatidylcholine 34:2 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
cylindrospermopsin	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
Leflunomide	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Dimethyl Sulfoxide	increases expression	1
Methyl Methanesulfonate	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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