METTL1

Summary

METTL1 (methyltransferase 1, tRNA methylguanosine, HGNC:7030) is a protein-coding gene on chromosome 12q14.1, encoding tRNA (guanine-N(7)-)-methyltransferase (Q9UBP6). Catalytic component of METTL1-WDR4 methyltransferase complex that mediates the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs). It is a selective cancer dependency (DepMap: 54.4% of cell lines).

This gene is similar in sequence to the S. cerevisiae YDL201w gene. The gene product contains a conserved S-adenosylmethionine-binding motif and is inactivated by phosphorylation. Alternative splice variants encoding different protein isoforms have been described for this gene. A pseudogene has been identified on chromosome X.

Source: NCBI Gene 4234 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 49 total
• Cancer dependency (DepMap): dependent in 54.4% of screened cell lines
• MANE Select transcript: NM_005371

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7030
Approved symbol	METTL1
Name	methyltransferase 1, tRNA methylguanosine
Location	12q14.1
Locus type	gene with protein product
Status	Approved
Aliases	TRM8, TRMT8
Ensembl gene	ENSG00000037897
Ensembl biotype	protein_coding
OMIM	604466
Entrez	4234

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000257848, ENST00000324871, ENST00000547653, ENST00000548504, ENST00000548681, ENST00000549773, ENST00000551117, ENST00000553125, ENST00000927433, ENST00000966255

RefSeq mRNA: 2 — MANE Select: NM_005371 NM_005371, NM_023033

CCDS: CCDS8955, CCDS8956

Canonical transcript exons

ENST00000324871 — 6 exons

Exon	Start	End
ENSE00001816099	57771974	57772105
ENSE00001948796	57768471	57769151
ENSE00003469427	57769303	57769404
ENSE00003492205	57769565	57769678
ENSE00003652541	57769772	57769956
ENSE00003675966	57771094	57771257

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 92.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.4513 / max 338.3509, expressed in 1790 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131761	15.4513	1790

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	92.44	silver quality
body of pancreas	UBERON:0001150	91.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.13	gold quality
pancreatic ductal cell	CL:0002079	89.27	gold quality
left adrenal gland cortex	UBERON:0035825	89.07	gold quality
left adrenal gland	UBERON:0001234	88.86	gold quality
right adrenal gland	UBERON:0001233	88.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.55	gold quality
pancreas	UBERON:0001264	88.37	gold quality
right lobe of thyroid gland	UBERON:0001119	87.57	gold quality
right adrenal gland cortex	UBERON:0035827	87.47	gold quality
stromal cell of endometrium	CL:0002255	87.03	gold quality
left lobe of thyroid gland	UBERON:0001120	87.02	gold quality
adrenal cortex	UBERON:0001235	86.76	gold quality
adrenal gland	UBERON:0002369	86.76	gold quality
adenohypophysis	UBERON:0002196	86.25	gold quality
right lobe of liver	UBERON:0001114	86.22	gold quality
islet of Langerhans	UBERON:0000006	86.11	gold quality
mucosa of transverse colon	UBERON:0004991	86.09	gold quality
left uterine tube	UBERON:0001303	85.91	gold quality
metanephros cortex	UBERON:0010533	85.88	gold quality
thyroid gland	UBERON:0002046	85.57	gold quality
adult mammalian kidney	UBERON:0000082	85.50	gold quality
omental fat pad	UBERON:0010414	84.70	gold quality
peritoneum	UBERON:0002358	84.64	gold quality
gastrocnemius	UBERON:0001388	84.55	gold quality
right ovary	UBERON:0002118	84.40	gold quality
esophagus mucosa	UBERON:0002469	84.40	gold quality
left ovary	UBERON:0002119	84.17	gold quality
right uterine tube	UBERON:0001302	84.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

21 targeting METTL1, 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-4789-3P	99.99	70.75	2484
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4795-5P	99.11	66.90	876
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-4308	97.56	67.13	1385
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 54.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells (PMID:25233213)
• The results identify METTL1-dependent N7-methylation of guanosine as a new RNA modification pathway that regulates miRNA structure, biogenesis, and cell migration. (PMID:31031083)
• METTL1 acts as a methyltransferase for a subset of internal N(7)-methylguanosine sites in mRNA. (PMID:31031084)
• METTL1 promotes cell proliferation and migration in HCC. METTL1 exerts oncogenic activities via suppression of PTEN signaling. (PMID:31463732)
• METTL1 limits differentiation and functioning of EPCs derived from human-induced pluripotent stem cells through a MAPK/ERK pathway. (PMID:32430183)
• METTL1-mediated m(7)G methylation maintains pluripotency in human stem cells and limits mesoderm differentiation and vascular development. (PMID:32698871)
• N(7)-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression. (PMID:34352206)
• METTL1-mediated m(7)G modification of Arg-TCT tRNA drives oncogenic transformation. (PMID:34352207)
• METTL1/WDR4-mediated m(7)G tRNA modifications and m(7)G codon usage promote mRNA translation and lung cancer progression. (PMID:34371184)
• METTL1 promotes hepatocarcinogenesis via m(7) G tRNA modification-dependent translation control. (PMID:34898034)
• METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma. (PMID:36102722)
• Structures and mechanisms of tRNA methylation by METTL1-WDR4. (PMID:36599982)
• Structural basis of regulated m[7]G tRNA modification by METTL1-WDR4. (PMID:36599985)
• Association of RNA m[7]G Modification Gene Polymorphisms with Pediatric Glioma Risk. (PMID:36733406)
• METTL1/WDR4-mediated tRNA m[7]G modification and mRNA translation control promote oncogenesis and doxorubicin resistance. (PMID:37185458)
• METTL1 gene polymorphisms and Wilms tumor susceptibility in Chinese children: A five-center case-control study. (PMID:37232474)
• P300/SP1 complex mediating elevated METTL1 regulates CDK14 mRNA stability via internal m7G modification in CRPC. (PMID:37599359)
• N6-methyladenosine-induced METTL1 promotes tumor proliferation via CDK4. (PMID:37694982)
• Metabolic reprogramming driven by METTL1-mediated tRNA m7G modification promotes acquired anlotinib resistance in oral squamous cell carcinoma. (PMID:38280546)
• METTL1 facilitates ameloblastoma invasive growth via MAPK signaling pathway. (PMID:38309318)
• WDR4 promotes HCC pathogenesis through N[7]-methylguanosine by regulating and interacting with METTL1. (PMID:38493882)
• The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9-Mediated Splicing of NFATc4. (PMID:38810124)
• METTL1-mediated tRNA m[7]G methylation and translational dysfunction restricts breast cancer tumorigenesis by fueling cell cycle blockade. (PMID:38822363)
• METTL1/FOXM1 promotes lung adenocarcinoma progression and gefitinib resistance by inhibiting PTPN13 expression. (PMID:38967523)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mettl1	ENSDARG00000076518
mus_musculus	Mettl1	ENSMUSG00000006732
rattus_norvegicus	Mettl1	ENSRNOG00000047895
drosophila_melanogaster	CG4045	FBGN0025629
caenorhabditis_elegans		WBGENE00012205

Protein

Protein identifiers

tRNA (guanine-N(7)-)-methyltransferase — Q9UBP6 (reviewed: Q9UBP6)

Alternative names: Methyltransferase-like protein 1, mRNA (guanine-N(7)-)-methyltransferase, miRNA (guanine-N(7)-)-methyltransferase, tRNA (guanine(46)-N(7))-methyltransferase, tRNA(m7G46)-methyltransferase

All UniProt accessions (5): Q9UBP6, F8VSD9, H0YHU4, H0YHX0, H0YIH0

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic component of METTL1-WDR4 methyltransferase complex that mediates the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs). Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5’-RAGGU-3’ motif within the variable loop. M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay. Also acts as a methyltransferase for a subset of internal N(7)-methylguanine in mRNAs. Internal N(7)-methylguanine methylation of mRNAs in response to stress promotes their relocalization to stress granules, thereby suppressing their translation. Also methylates a specific subset of miRNAs, such as let-7. N(7)-methylguanine methylation of let-7 miRNA promotes let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA). Acts as a regulator of embryonic stem cell self-renewal and differentiation.

Subunit / interactions. Catalytic component of the METTL1-WDR4 complex, composed of METTL1 and WDR4.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylation at Ser-27 by PKB/AKT1 inactivates its methyltransferase activity via a steric interference mechanism in the active site that locally disrupts the catalytic center. Phosphorylation at Ser-27 does not affect the interaction with WDR4.

Domain organisation. Upon tRNA-binding, the alphaC region transforms into a helix, which together with the alpha6 helix secures both ends of the tRNA variable loop. The N-terminal disordered region is part of the catalytic pocket and essential for methyltransferase activity: upon S-adenosyl-L-methionine- and tRNA-binding, the N-terminal disordered region becomes ordered, sandwiched between the bound cofactor and the tRNA, and the WDR4 C-terminus attaches to the METTL1 N-terminus to stabilize the bound tRNA together. Together with WDR4, which also binds tRNAs, tRNAs undergo bending to facilitate G46 flipping into the catalytic pocket to be modified.

Induction. Amplified and overexpressed in a number of cancers and is associated with poor prognosis (at protein level).

Pathway. tRNA modification; N(7)-methylguanine-tRNA biosynthesis.

Miscellaneous. In the context of cancer, overexpression of the METTL1-WDR4 methyltransferase complex promotes cancer progression by driving oncogenic transformation. Drives oncogenesis by mediating the formation of N(7)-methylguanine at position 46 (m7G46) in some tRNAs, in particular Arg-TCT-4-1 (TRR-TCT4-1), leading to increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. TrmB family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBP6-1	1	yes
Q9UBP6-2	2

RefSeq proteins (2): NP_005362, NP_075422 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003358	tRNA_(Gua-N-7)_MeTrfase_Trmb	Family
IPR025763	Trm8_euk	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF02390

Catalyzed reactions (Rhea), 3 shown:

• guanosine(46) in tRNA + S-adenosyl-L-methionine = N(7)-methylguanosine(46) in tRNA + S-adenosyl-L-homocysteine (RHEA:42708)
• a guanosine in mRNA + S-adenosyl-L-methionine = an N(7)-methylguanosine in mRNA + S-adenosyl-L-homocysteine (RHEA:60508)
• a guanosine in miRNA + S-adenosyl-L-methionine = an N(7)-methylguanosine in miRNA + S-adenosyl-L-homocysteine (RHEA:60512)

UniProt features (81 total): mutagenesis site 26, binding site 17, helix 12, strand 9, turn 6, region of interest 3, modified residue 2, splice variant 2, initiator methionine 1, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
3CKK	X-RAY DIFFRACTION	1.55
7OGJ	X-RAY DIFFRACTION	1.59
8H0N	X-RAY DIFFRACTION	1.8
7PL1	X-RAY DIFFRACTION	1.85
8D5B	X-RAY DIFFRACTION	1.93
8D59	X-RAY DIFFRACTION	2.26
8D58	X-RAY DIFFRACTION	2.47
7U20	X-RAY DIFFRACTION	3.1
8CTH	ELECTRON MICROSCOPY	3.3
8EG0	ELECTRON MICROSCOPY	3.53
8CTI	ELECTRON MICROSCOPY	3.6
8D9K	ELECTRON MICROSCOPY	3.72
8D9L	ELECTRON MICROSCOPY	4.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBP6-F1	88.42	0.74

Functional residue map

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

Catalytic / active sites (1): 163

Ligand- & substrate-binding residues (17): 108; 109; 109; 140; 140; 141; 141; 160; 160; 238; 238; 240 …

Post-translational modifications (2): 2, 27

Mutagenesis-validated functional residues (26):

Position	Phenotype
18	strongly reduced methyltransferase activity.
24	abolished methyltransferase activity.
27	abolished phosphorylation; does not affect methyltransferase activity.
27	mimics phosphorylation; abolished affect methyltransferase activity.
27	abolished methyltransferase activity.
29	strongly reduced methyltransferase activity.
40	abolished interaction with wdr4; when associated with d-143, d-151 and d-172.
107–109	abolished rna methyltransferase activity.
109	abolished methyltransferase activity.
111	slightly reduced methyltransferase activity.
118	slightly reduced methyltransferase activity.
143	abolished methyltransferase activity.
143	abolished interaction with wdr4; when associated with d-40, d-151 and d-172.
151	abolished interaction with wdr4; when associated with d-40, d-143 and d-172.
160–163	abolished methyltransferase activity.
163	abolished methyltransferase activity.
165	abolished trna-binding; when associated with a-167, a-170, a-243 and a-246.
167	abolished methyltransferase activity. abolished trna-binding; when associated with a-165, a-170, a-243 and a-246.
168	does not affect methyltransferase activity.
170	abolished trna-binding; when associated with a-165, a-167, a-243 and a-246.
172	abolished interaction with wdr4; when associated with d-40, d-143 and d-151.
173	strongly reduced methyltransferase activity.
199	abolished methyltransferase activity.
240	abolished methyltransferase activity.
243	slightly reduced trna-binding. abolished trna-binding; when associated with a-165, a-167, a-170 and a-246. strongly redu

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol

MSigDB gene sets: 202 (showing top): GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_RNA_METHYLATION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RNA_MODIFICATION, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_TRNA_METHYLATION, NIKOLSKY_BREAST_CANCER_12Q13_Q21_AMPLICON, DODD_NASOPHARYNGEAL_CARCINOMA_UP, DANG_BOUND_BY_MYC, GOBP_METHYLATION

GO Biological Process (11): tRNA modification (GO:0006400), tRNA methylation (GO:0030488), cellular response to stress (GO:0033554), RNA (guanine-N7)-methylation (GO:0036265), tRNA stabilization (GO:0036416), tRNA (guanine-N7)-methylation (GO:0106004), tRNA processing (GO:0008033), intracellular mRNA localization (GO:0008298), methylation (GO:0032259), stress granule assembly (GO:0034063), mRNA transport (GO:0051028)

GO Molecular Function (7): tRNA binding (GO:0000049), tRNA (guanine(46)-N7)-methyltransferase activity (GO:0008176), internal mRNA (guanine-N7-)-methyltransferase activity (GO:0160090), RNA binding (GO:0003723), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), tRNA methyltransferase complex (GO:0043527), tRNA (m7G46) methyltransferase complex (GO:0106143)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA methylation	2
RNA (guanine-N7)-methylation	2
nuclear lumen	2
cellular anatomical structure	2
tRNA processing	1
RNA modification	1
tRNA modification	1
response to stress	1
cellular response to stimulus	1
regulation of tRNA stability	1
RNA stabilization	1
negative regulation of tRNA catabolic process	1
tRNA methylation	1
RNA processing	1
tRNA metabolic process	1
RNA localization	1
metabolic process	1
membraneless organelle assembly	1
RNA transport	1
RNA binding	1
tRNA (guanine) methyltransferase activity	1
tRNA (guanine-N7)-methylation	1
mRNA methyltransferase activity	1
nucleic acid binding	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
cytoplasm	1
methyltransferase complex	1
tRNA methyltransferase complex	1

Protein interactions and networks

STRING

2496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
METTL1	WDR4	P57081	998
METTL1	NSUN2	Q08J23	768
METTL1	TRMT6	Q9UJA5	744
METTL1	TRMT61A	Q96FX7	726
METTL1	BUD23	O43709	713
METTL1	TRMT112	Q9UI30	710
METTL1	TRMT10A	Q8TBZ6	709
METTL1	TRMT1	Q9NXH9	709
METTL1	METTL3	Q86U44	695
METTL1	TRMT44	Q8IYL2	689
METTL1	MRM3	Q9HC36	685
METTL1	TSFM	P43897	678
METTL1	FTSJ1	Q9UET6	676
METTL1	CYP27B1	O15528	667
METTL1	TRMT11	Q7Z4G4	667

IntAct

22 interactions, top by confidence:

A	B	Type	Score
WDR4	METTL1	psi-mi:“MI:0915”(physical association)	0.910
METTL1	WDR4	psi-mi:“MI:0915”(physical association)	0.910
WDR4	PCNA	psi-mi:“MI:0914”(association)	0.460
METTL1	WDR4	psi-mi:“MI:0915”(physical association)	0.400
METTL1	RPSA2	psi-mi:“MI:0915”(physical association)	0.400
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
TP53BP1	BCKDK	psi-mi:“MI:0914”(association)	0.350
SSB	RPS3A	psi-mi:“MI:0914”(association)	0.350
	GTPBP1	psi-mi:“MI:0914”(association)	0.350
METTL1	ZWINT	psi-mi:“MI:0914”(association)	0.350
METTL1	WDR4	psi-mi:“MI:0915”(physical association)	0.000
WDR4	METTL1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (72): METTL1 (Biochemical Activity), TRM8 (Synthetic Rescue), WDR4 (Affinity Capture-Western), METTL1 (Affinity Capture-Western), WDR4 (Two-hybrid), WDR4 (Affinity Capture-MS), WDR4 (Two-hybrid), APEX1 (Co-fractionation), C15orf40 (Co-fractionation), NHP2L1 (Co-fractionation), PPA2 (Co-fractionation), TPD52L2 (Co-fractionation), TRMT61A (Co-fractionation), TSNAX (Co-fractionation), WDR4 (Co-fractionation)

ESM2 similar proteins: A0A1V6NXN7, A1CIF1, A1CWA9, A2Q9E4, A3LS77, A4QX49, A4RJA0, A5E7T4, A6S8E7, A8N2M6, B0Y4I9, B2AR91, B4R338, J4VSL0, J4W0D1, P0CM18, P0CS06, P0CS07, P0CS80, P0CS81, Q0CF43, Q0CT71, Q0TZT0, Q0UHM7, Q28H76, Q2GS86, Q2GZU7, Q2U6Q1, Q2UJ66, Q2UU72, Q2YDF1, Q4P0Y5, Q4WCV5, Q4WE58, Q4WHY5, Q4WJX7, Q4WQB9, Q4WUT7, Q5A692, Q5ASK9

Diamond homologs: A0K1I7, A0K594, A0PMW8, A1CIF1, A1CWA9, A1KCM8, A1KUF5, A1T1J8, A1WIH0, A2Q9E4, A2YB34, A3LS77, A4JC58, A4QHQ6, A4T3S4, A5DC23, A5E7T4, A6S8E7, A6ZXD2, A7TT36, A8NFF0, A8WTA7, A9LZQ8, A9UMM1, B0WSB8, B0Y4I9, B1VEE1, B2AR91, B2U7E2, B3LH81, B3MYY4, B3P8V8, B4H4I3, B4I9N7, B4JLU7, B4L529, B4M703, B4N278, B4Q1B6, B4R338

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RPS6KA1	down-regulates	METTL1	phosphorylation
AKT	down-regulates	METTL1	phosphorylation
AKT1	down-regulates	METTL1	phosphorylation
RPS6K	down-regulates	METTL1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1176 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57769148:CACT:C	acceptor_gain	1.0000
12:57769150:CT:C	acceptor_gain	1.0000
12:57769152:C:CC	acceptor_gain	1.0000
12:57769297:ACT:A	donor_loss	1.0000
12:57769298:CTC:C	donor_loss	1.0000
12:57769299:TCA:T	donor_loss	1.0000
12:57769301:ACCAG:A	donor_loss	1.0000
12:57769456:C:CT	acceptor_gain	1.0000
12:57769456:C:T	acceptor_gain	1.0000
12:57769560:CTCA:C	donor_loss	1.0000
12:57769563:A:AC	donor_gain	1.0000
12:57769563:A:T	donor_loss	1.0000
12:57769563:AC:A	donor_gain	1.0000
12:57769563:ACC:A	donor_gain	1.0000
12:57769564:C:CA	donor_loss	1.0000
12:57769564:C:CC	donor_gain	1.0000
12:57769564:CC:C	donor_gain	1.0000
12:57769564:CCC:C	donor_gain	1.0000
12:57769576:G:C	donor_gain	1.0000
12:57769643:A:AC	acceptor_gain	1.0000
12:57769643:A:C	acceptor_gain	1.0000
12:57769651:C:CT	acceptor_gain	1.0000
12:57769652:G:T	acceptor_gain	1.0000
12:57769675:TCAG:T	acceptor_gain	1.0000
12:57769676:CAG:C	acceptor_gain	1.0000
12:57769676:CAGC:C	acceptor_gain	1.0000
12:57769677:AG:A	acceptor_gain	1.0000
12:57769678:GCTG:G	acceptor_loss	1.0000
12:57769679:C:CC	acceptor_gain	1.0000
12:57769680:T:A	acceptor_loss	1.0000

AlphaMissense

1795 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:57769637:C:A	K167N	1.000
12:57769637:C:G	K167N	1.000
12:57769640:G:C	F166L	1.000
12:57769640:G:T	F166L	1.000
12:57769642:A:G	F166L	1.000
12:57769382:T:A	D199V	0.999
12:57769385:G:A	T198I	0.999
12:57769617:C:G	R174P	0.999
12:57769628:C:A	K170N	0.999
12:57769628:C:G	K170N	0.999
12:57769630:T:C	K170E	0.999
12:57769639:T:C	K167E	0.999
12:57769641:A:G	F166S	0.999
12:57769645:G:C	H165D	0.999
12:57769650:T:C	D163G	0.999
12:57769655:G:C	F161L	0.999
12:57769655:G:T	F161L	0.999
12:57769657:A:G	F161L	0.999
12:57769811:A:C	N140K	0.999
12:57769811:A:T	N140K	0.999
12:57769875:C:G	R119P	0.999
12:57769911:T:A	E107V	0.999
12:57771111:C:T	G86D	0.999
12:57771117:C:T	G84D	0.999
12:57771998:G:T	P29H	0.999
12:57772000:G:C	N28K	0.999
12:57772000:G:T	N28K	0.999
12:57772006:G:C	H26Q	0.999
12:57772006:G:T	H26Q	0.999
12:57772008:G:C	H26D	0.999

dbSNP variants (sampled 300 via entrez): RS1001780691 (12:57768566 A>C,G), RS1003559139 (12:57774064 T>C), RS1005442990 (12:57770320 CTTAT>C), RS1005912480 (12:57771561 A>C), RS1007583468 (12:57768207 G>A,T), RS1008184238 (12:57771273 C>T), RS1008246388 (12:57771875 C>G,T), RS1008714788 (12:57768808 T>C), RS1009959274 (12:57772493 T>C), RS1010580061 (12:57772661 C>A,T), RS1012086281 (12:57772245 G>A,C), RS1012829879 (12:57773204 G>C), RS1012928404 (12:57768137 C>A,T), RS1013082527 (12:57773421 G>T), RS1013259673 (12:57769541 A>C)

Disease associations

OMIM: gene MIM:604466 | 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
GCST000425_3	Multiple sclerosis	5.000000e-11
GCST010703_209	Brain morphology (MOSTest)	2.000000e-11
GCST012226_323	Waist circumference adjusted for body mass index	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference

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
rs10877012	CYP27B1, METTL1	3	2.00	2	peginterferon alfa-2b;ribavirin;deferasirox

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Nickel	increases expression	2
Tretinoin	decreases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
beta-lapachone	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases reaction, affects binding	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cadmium	decreases expression	1
Caffeine	increases phosphorylation	1
Coumestrol	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7GY	Ubigene HEK293T METTL1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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