TOMT

Summary

TOMT (transmembrane O-methyltransferase, HGNC:55527) is a protein-coding gene on chromosome 11q13.4, encoding Transmembrane O-methyltransferase (Q8WZ04). Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones.

This gene encodes a catechol-O-methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to a hydroxyl group of catechols and is essential for auditory and vestibular function. Mutations in this gene have been associated with nonsyndromic deafness. Readthrough transcription is observed across this gene and the adjacent leucine-rich repeat containing 51 gene. A third locus (GeneID:220074) is defined to represent the readthrough transcripts.

Source: NCBI Gene 120356740 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 19 total — 3 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001393500

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:55527
Approved symbol	TOMT
Name	transmembrane O-methyltransferase
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	COMT2
Ensembl gene	ENSG00000284844
Ensembl biotype	protein_coding
Entrez	120356740

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000541899, ENST00000864603

RefSeq mRNA: 1 — MANE Select: NM_001393500 NM_001393500

CCDS: CCDS91529

Canonical transcript exons

ENST00000541899 — 3 exons

Exon	Start	End
ENSE00002302030	72105924	72106210
ENSE00003818163	72107923	72108119
ENSE00003827728	72108605	72109596

Expression profiles

Bgee: expression breadth broad, 14 present calls, max score 67.31.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	67.31	gold quality
bone marrow cell	CL:0002092	44.35	gold quality
ventricular zone	UBERON:0003053	43.36	gold quality
ganglionic eminence	UBERON:0004023	41.10	silver quality
cortical plate	UBERON:0005343	39.74	gold quality
duodenum	UBERON:0002114	37.80	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
sural nerve	UBERON:0015488	37.13	gold quality
muscle tissue	UBERON:0002385	36.97	silver quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
lymph node	UBERON:0000029	30.80	gold quality
adrenal tissue	UBERON:0018303	30.70	gold quality
urinary bladder	UBERON:0001255	30.05	gold quality
prefrontal cortex	UBERON:0000451	29.91	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
islet of Langerhans	UBERON:0000006	29.36	silver quality
smooth muscle tissue	UBERON:0001135	29.05	silver quality
endometrium	UBERON:0001295	28.66	gold quality
gall bladder	UBERON:0002110	28.46	gold quality
fundus of stomach	UBERON:0001160	27.73	gold quality
right testis	UBERON:0004534	27.67	silver quality
tonsil	UBERON:0002372	27.05	gold quality
vermiform appendix	UBERON:0001154	26.42	gold quality
testis	UBERON:0000473	26.07	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	25.89	gold quality
placenta	UBERON:0001987	25.81	gold quality
left testis	UBERON:0004533	25.76	silver quality
adult mammalian kidney	UBERON:0000082	25.50	gold quality
leukocyte	CL:0000738	25.44	gold quality
monocyte	CL:0000576	25.23	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.16

Regulation

Is transcription factor: no

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	tomt	ENSDARG00000115463
mus_musculus	Tomt	ENSMUSG00000078630
rattus_norvegicus	Lrtomt	ENSRNOG00000023434
caenorhabditis_elegans		WBGENE00012518
caenorhabditis_elegans		WBGENE00021487
caenorhabditis_elegans		WBGENE00021491
caenorhabditis_elegans		WBGENE00021492

Paralogs (2): COMT (ENSG00000093010), COMTD1 (ENSG00000165644)

Protein

Protein identifiers

Transmembrane O-methyltransferase — Q8WZ04 (reviewed: Q8WZ04)

Alternative names: Catechol O-methyltransferase 2, Protein LRTOMT2

All UniProt accessions (1): A0A2R8Y5M8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Required for auditory function. Component of the cochlear hair cell’s mechanotransduction (MET) machinery. Involved in the assembly of the asymmetric tip-link MET complex. Required for transportation of TMC1 and TMC2 proteins into the mechanically sensitive stereocilia of the hair cells. The function in MET is independent of the enzymatic activity.

Subunit / interactions. Interacts with LHFPL5, PCDH15, TMC1, TMC2 and TMIE. Interacts directly with TMC1. The interaction of TOMT with TMC1 and TMC2 is required for the transportation of TMC1/2 into the stereocilia of hair cells.

Subcellular location. Membrane Cytoplasm. Endoplasmic reticulum.

Disease relevance. Deafness, autosomal recessive, 63 (DFNB63) [MIM:611451] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. LRRC51 and TOMT were originally considered as alternative reading frames, LRTOMT1 and LRTOMT2 of the same LRTOMT gene in primates.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-dependent O-methyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WZ04-1	1, D'	yes
Q8WZ04-2	2, E'

RefSeq proteins (1): NP_001380429* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002935	SAM_O-MeTrfase	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF01596

Catalyzed reactions (Rhea), 1 shown:

• a catechol + S-adenosyl-L-methionine = a guaiacol + S-adenosyl-L-homocysteine + H(+) (RHEA:17877)

UniProt features (15 total): sequence variant 7, binding site 5, chain 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WZ04-F1	90.73	0.86

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 (5): 137; 139–140; 145; 163; 193

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-379397	Enzymatic degradation of dopamine by COMT

MSigDB gene sets: 1 (showing top): chr11q13

GO Biological Process (9): sensory perception of sound (GO:0007605), methylation (GO:0032259), developmental process (GO:0032502), dopamine metabolic process (GO:0042417), dopamine catabolic process (GO:0042420), catecholamine catabolic process (GO:0042424), auditory receptor cell development (GO:0060117), catecholamine metabolic process (GO:0006584), positive regulation of protein import (GO:1904591)

GO Molecular Function (4): catechol O-methyltransferase activity (GO:0016206), methyltransferase activity (GO:0008168), O-methyltransferase activity (GO:0008171), transferase activity (GO:0016740)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), cytoplasm (GO:0005737), apical part of cell (GO:0045177)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Dopamine clearance from the synaptic cleft	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catecholamine metabolic process	2
cellular anatomical structure	2
sensory perception of mechanical stimulus	1
metabolic process	1
biological_process	1
dopamine metabolic process	1
catecholamine catabolic process	1
catechol-containing compound catabolic process	1
biogenic amine catabolic process	1
inner ear auditory receptor cell differentiation	1
inner ear receptor cell development	1
biogenic amine metabolic process	1
catechol-containing compound metabolic process	1
protein import	1
positive regulation of protein transport	1
regulation of protein import	1
O-methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1440 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOMT	MAOB	P27338	897
TOMT	MAOA	P21397	894
TOMT	SLC6A3	Q01959	781
TOMT	DDC	P20711	772
TOMT	TH	P07101	724
TOMT	SLC6A4	P31645	717
TOMT	DRD4	P21917	699
TOMT	DRD2	P14416	696
TOMT	CYP1B1	Q16678	670
TOMT	DBH	P09172	667
TOMT	SHANK2	Q9UPX8	649
TOMT	PNMT	P11086	638
TOMT	ANKK1	Q8NFD2	633
TOMT	SLC18A2	Q05940	625
TOMT	BDNF	P23560	620

IntAct

2 interactions, top by confidence:

A	B	Type	Score
TOMT	JOSD2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (6): JOSD2 (Affinity Capture-MS), LRTOMT (Affinity Capture-RNA), JOSD2 (Affinity Capture-MS), LRTOMT (Affinity Capture-RNA), LRTOMT (Affinity Capture-RNA), LRTOMT (Affinity Capture-RNA)

ESM2 similar proteins: A0A193KX02, A0A397HK53, A1Y9I9, A4IG53, A5WWC6, B6CZ46, B6CZ56, B6CZ62, B8NR70, L0TAD5, O42898, P37059, P55205, P58781, P86243, Q0IIS3, Q0P464, Q28C60, Q28DI5, Q2KHV5, Q2VQV9, Q32LS6, Q3V1F8, Q4V339, Q5JTY5, Q5RIA9, Q5XI69, Q5XI79, Q66KL0, Q68EZ3, Q6DCK1, Q6GQ37, Q6PE54, Q6Q2C2, Q6TL19, Q7L592, Q7L5L3, Q8IUF1, Q8IX18, Q8NKC1

Diamond homologs: A0A193KX02, A1Y9I9, A4IG53, A7MBI7, B6CZ46, B6CZ56, B6CZ62, F4ZGF2, G8T6H8, L0TAD5, O42898, O88587, P21964, P22734, P86243, Q00719, Q5H879, Q8NKC1, Q8WZ04, Q99028, B8NI24, O07431, Q9YDA1, A2BKH8, O26915, O27962, Q57636, Q86VU5, Q8TYL4, A6TCI9, B2RK25, B5XNG1, O32036, Q7MVG0, Q8A9H7, Q9XGD5, S5DQS6, Q9ZTT5, A0A0S2UWA5, A0A0S2UWC9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	10
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1804950	NM_001145308.5(LRTOMT):c.199C>T (p.Arg67Ter)	Pathogenic
3601215	NM_001145308.5(LRTOMT):c.307del (p.Asp103fs)	Pathogenic
546	NM_001145308.5(LRTOMT):c.333C>G (p.Tyr111Ter)	Pathogenic
3601214	NM_001145308.5(LRTOMT):c.242G>C (p.Arg81Pro)	Likely pathogenic

SpliceAI

1168 predictions. Top by Δscore:

Variant	Effect	Δscore
11:72108603:AGGT:A	acceptor_gain	1.0000
11:72108604:GGTG:G	acceptor_gain	1.0000
11:72110219:CATAG:C	acceptor_gain	1.0000
11:72110221:TAGTG:T	acceptor_gain	1.0000
11:72110222:AGTG:A	acceptor_gain	1.0000
11:72110223:GTG:G	acceptor_gain	1.0000
11:72110224:TG:T	acceptor_gain	1.0000
11:72110224:TGCT:T	acceptor_loss	1.0000
11:72110226:C:A	acceptor_loss	1.0000
11:72110226:C:CC	acceptor_gain	1.0000
11:72110227:T:A	acceptor_loss	1.0000
11:72110539:CTCA:C	donor_loss	1.0000
11:72110540:TCAC:T	donor_loss	1.0000
11:72110541:CACCT:C	donor_loss	1.0000
11:72110542:A:AC	donor_gain	1.0000
11:72110542:A:C	donor_loss	1.0000
11:72110543:C:CC	donor_gain	1.0000
11:72110543:CCT:C	donor_gain	1.0000
11:72105969:ATT:A	acceptor_gain	0.9900
11:72105986:T:TA	acceptor_gain	0.9900
11:72106206:CAAAG:C	donor_loss	0.9900
11:72106207:AAAGG:A	donor_loss	0.9900
11:72106209:AGG:A	donor_loss	0.9900
11:72106211:GTC:G	donor_loss	0.9900
11:72106212:T:G	donor_loss	0.9900
11:72108599:CCACA:C	acceptor_loss	0.9900
11:72108600:CACA:C	acceptor_loss	0.9900
11:72108601:ACAGG:A	acceptor_loss	0.9900
11:72108602:CA:C	acceptor_loss	0.9900
11:72108603:A:AG	acceptor_gain	0.9900

AlphaMissense

1616 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:72108807:T:C	F220S	0.989
11:72107992:G:A	G110E	0.987
11:72108723:T:C	L192P	0.984
11:72108903:T:C	L252P	0.983
11:72108836:T:G	Y230D	0.981
11:72108774:C:A	A209D	0.974
11:72106165:T:A	W72R	0.972
11:72106165:T:C	W72R	0.972
11:72108897:C:A	A250D	0.972
11:72108768:T:A	V207E	0.971
11:72108639:T:C	I164T	0.969
11:72108837:A:C	Y230S	0.969
11:72108639:T:A	I164N	0.966
11:72108806:T:C	F220L	0.964
11:72108808:C:A	F220L	0.964
11:72108808:C:G	F220L	0.964
11:72108836:T:A	Y230N	0.962
11:72108639:T:G	I164S	0.960
11:72108903:T:A	L252H	0.960
11:72107971:T:C	L103P	0.958
11:72108807:T:G	F220C	0.957
11:72106208:A:T	K86I	0.955
11:72107991:G:A	G110R	0.955
11:72107991:G:C	G110R	0.955
11:72105983:C:G	P11R	0.954
11:72108684:T:A	V179E	0.951
11:72106167:G:C	W72C	0.950
11:72106167:G:T	W72C	0.950
11:72107971:T:G	L103R	0.950
11:72108046:C:T	T128I	0.950

dbSNP variants (sampled 300 via entrez): RS1001585414 (11:72104907 T>A,C), RS1003700981 (11:72108810 T>C,G), RS1004173882 (11:72104013 C>G,T), RS1005768038 (11:72108834 G>A), RS1005820299 (11:72109171 T>C), RS1005909665 (11:72109348 G>T), RS1006100075 (11:72107401 G>A), RS1006458849 (11:72109716 G>C), RS1007526596 (11:72106330 CTT>C,CT,CTTT), RS1008617007 (11:72109576 A>G), RS1009316091 (11:72104632 ACT>A), RS1010045590 (11:72109758 T>C), RS1010685773 (11:72109745 G>A,T), RS1012740858 (11:72106443 G>C), RS1012991988 (11:72105594 G>A)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:611451

GenCC curated gene-disease

Mondo (1): autosomal recessive nonsyndromic hearing loss 63 (MONDO:0012670)

Orphanet (1): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566951	Deafness, Autosomal Recessive 63 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Clinical trials (associated diseases)

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