FMO3

Summary

FMO3 (flavin containing dimethylaniline monoxygenase 3, HGNC:3771) is a protein-coding gene on chromosome 1q24.3, encoding Flavin-containing monooxygenase 3 (P31513). Essential hepatic enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including drugs as well as dietary compounds.

Flavin-containing monooxygenases (FMO) are an important class of drug-metabolizing enzymes that catalyze the NADPH-dependent oxygenation of various nitrogen-,sulfur-, and phosphorous-containing xenobiotics such as therapeutic drugs, dietary compounds, pesticides, and other foreign compounds. The human FMO gene family is composed of 5 genes and multiple pseudogenes. FMO members have distinct developmental- and tissue-specific expression patterns. The expression of this FMO3 gene, the major FMO expressed in adult liver, can vary up to 20-fold between individuals. This inter-individual variation in FMO3 expression levels is likely to have significant effects on the rate at which xenobiotics are metabolised and, therefore, is of considerable interest to the pharmaceutical industry. This transmembrane protein localizes to the endoplasmic reticulum of many tissues. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. Mutations in this gene cause the disorder trimethylaminuria (TMAu) which is characterized by the accumulation and excretion of unmetabolized trimethylamine and a distinctive body odor. In healthy individuals, trimethylamine is primarily converted to the non odorous trimethylamine N-oxide.

Source: NCBI Gene 2328 — RefSeq curated summary.

At a glance

• Gene–disease (curated): trimethylaminuria (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 313 total — 42 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_001002294

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3771
Approved symbol	FMO3
Name	flavin containing dimethylaniline monoxygenase 3
Location	1q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FMOII
Ensembl gene	ENSG00000007933
Ensembl biotype	protein_coding
OMIM	136132
Entrez	2328

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 16 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000367755, ENST00000472784, ENST00000478457, ENST00000479749, ENST00000530212, ENST00000534514, ENST00000896149, ENST00000896150, ENST00000896151, ENST00000896152, ENST00000896153, ENST00000896154, ENST00000896155, ENST00000896156, ENST00000896157, ENST00000896158, ENST00000896159, ENST00000896160, ENST00000896161, ENST00000896162

RefSeq mRNA: 4 — MANE Select: NM_001002294 NM_001002294, NM_001319173, NM_001319174, NM_006894

CCDS: CCDS1292

Canonical transcript exons

ENST00000367755 — 9 exons

Exon	Start	End
ENSE00000814539	171110798	171110997
ENSE00001151581	171116208	171116280
ENSE00001151588	171114007	171114362
ENSE00001151597	171108079	171108221
ENSE00001151608	171107675	171107837
ENSE00001317495	171117100	171117819
ENSE00002171185	171090905	171090981
ENSE00003702890	171103785	171103973
ENSE00003706723	171092653	171092790

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 98.81.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9710 / max 624.6712, expressed in 121 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6589	1.9139	119
6590	0.0205	11
6588	0.0201	9
6587	0.0165	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.81	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.23	gold quality
nasal cavity mucosa	UBERON:0001826	97.11	gold quality
liver	UBERON:0002107	96.91	gold quality
nasal cavity epithelium	UBERON:0005384	94.33	gold quality
right lung	UBERON:0002167	89.17	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.75	gold quality
bronchial epithelial cell	CL:0002328	83.56	gold quality
upper lobe of left lung	UBERON:0008952	82.98	gold quality
upper lobe of lung	UBERON:0008948	82.33	gold quality
right uterine tube	UBERON:0001302	82.23	gold quality
adipose tissue	UBERON:0001013	82.03	gold quality
connective tissue	UBERON:0002384	81.05	gold quality
epithelium of bronchus	UBERON:0002031	80.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.32	gold quality
bronchus	UBERON:0002185	79.71	gold quality
right adrenal gland cortex	UBERON:0035827	78.80	gold quality
omental fat pad	UBERON:0010414	78.41	gold quality
left adrenal gland cortex	UBERON:0035825	78.39	gold quality
visceral pleura	UBERON:0002401	78.38	gold quality
lung	UBERON:0002048	78.36	gold quality
peritoneum	UBERON:0002358	78.31	gold quality
adipose tissue of abdominal region	UBERON:0007808	77.84	gold quality
lower lobe of lung	UBERON:0008949	77.82	gold quality
left adrenal gland	UBERON:0001234	77.30	gold quality
adrenal cortex	UBERON:0001235	76.70	gold quality
calcaneal tendon	UBERON:0003701	76.69	gold quality
right adrenal gland	UBERON:0001233	76.44	gold quality
left uterine tube	UBERON:0001303	75.85	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-11	yes	50.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, DNMT1, HNF4A, NR1H4, PBX2, TCF3, TP53, USF1, VSX2, YY1

miRNA regulators (miRDB)

36 targeting FMO3, 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-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-3168	99.08	67.75	1384

Literature-anchored findings (GeneRIF, showing 40)

• These data suggest that birth is necessary, but not sufficient for the onset of FMO3 expression. A gender-independent increase in FMO3 expression was observed from 11 to 18 y of age. (PMID:11809920)
• two new polymorphisms, His132-FMO3 and Pro360-FMO3, were identified; the effect of the amino acid substitutions on the function of FMO3 was evaluated (PMID:12814961)
• Data show that the frequencies of FMO3 mutant alleles varied not only in different ethnic groups, but also in different populations that stemmed from the same ethnic group. (PMID:12903042)
• “..FMO3 appears to be the most important flavin-containing monoxygenase..in adult human liver. p. 574 “..human FMO3 appears to oxygenate nucleophilic heteroatom-containing substrates..” p. 576 (PMID:15203093)
• FMO3 displayed a significant, dominant liver-specific mRNA profile. (PMID:16183778)
• variants in the FMO3 gene do not predispose to essential hypertension in a cardiovascular disease population of 1649 individuals, 691(41.9%) of whom had a history of hypertension requiring drug treatment (PMID:16324215)
• Flavin-containing monooxygenase 3 (FMO3) is responsible for the majority of FMO-mediated xenobiotic metabolism in the adult human liver. (PMID:16481213)
• Genetic basis of trimethylaminuria is studied in Italian pedigrees and shows a spectrum of variation in the FM03 gene with 3 novel mutations: a de novo missense mutation, a deletion (G1182del) at codon 394 and a novel missense mutation (R238P). (PMID:16600650)
• The genotypes and allele frequencies of the MDR1/C3435T, FMO3/G488A, FMO3/A923G and CYP1A2/G-3860 A polymorphisms were not significantly different in cancer-free subjects and CRC patients. (PMID:16800822)
• The study is said to be the first report for significant single nucleotide polymorphisms of the FMO3 causing amino acid substitutions in Japanese trimethylaminuria patients. (PMID:16858129)
• As summarized in this review, FMO3 is apparently unique to the human, yet is the most abundant FMO family member in the adult human liver, whereas FMO1 dominates in most animal models. (PMID:16863467)
• Individuals homozygous for either of the nonsense mutations–Arg500Stop and/or Cys197Stop–alleles in the FMO3 gene can possess abnormal trimethylamine N-oxygenation. (PMID:16996766)
• results suggest that the effects of genetic variation of FMO3 could operate at the functional level for N- & S-oxygenation for typical FMO3 substrates (PMID:17142560)
• abnormal FMO3 capacity is caused by menstruation particularly in the presence, in homozygous form, of mild genetic variants such as [Glu158Lys; Glu308Gly] that cause a reduced FMO3 function (PMID:17257434)
• A homology model for FMO3 was constructed based on the crystal structure for yeast FMO which places the N61 residue alone, of the mutants analyzed here, in close proximity to the FAD catalytic center. (PMID:17531949)
• This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases. (PMID:17559352)
• Mutations of the FMO3 gene were investigated in Japanese trimethylaminuria that showed low FMO3 metabolic capacity. (PMID:17584019)
• FMO3 is the primary human adult liver FMO enzyme, but is developmentally regulated (PMID:17786630)
• TG100435 and TG100855 were interconverted metabolically. FMO3 seem to be the major N-oxidizing enzyme, whereas cytochrome P450 reductase seems to be responsible for the retroreduction reaction. (PMID:17881660)
• The results provide evidence that FMO3 has been the subject of balancing selection. (PMID:17885620)
• Site-directed mutagenesis studies suggest that the putative hepatic nuclear factor-4 (HNF-4) binding site and CCAAT box could be responsible cis-acting elements of the FMO3 gene in a Japanese population. (PMID:18305374)
• Localization of mutations in human FMO3 that are known to cause trimethylaminuria (fish-odor syndrome) in the elucidated FMO structure provides a structural explanation for their biological effects. (PMID:18443301)
• the combination of V187A/E158K mutations in FMO3, the enzyme activity is severely affected and possibly contributes to the trimethylaminuria observed. (PMID:19321370)
• considerable individual differences in FMO3 levels may exist in Japanese livers. The liver-enriched transcription factor HNF-4 appears to be a determinant of FMO3 expression in livers, as well as the ubiquitous factor NF-Y. (PMID:19571433)
• The identification in a family from northern Norway of a novel causative mutation of FMO3 gene causing trimethylaminuria, is described. (PMID:19577495)
• Distribution of functionally relevant FMO3 polymorphisms varies not only between ethnicities but also within (PMID:19761368)
• This study is the first to demonstrate a gene-environment interaction in SIDS. The findings suggest that the common polymorphism G472A of FMO3 could act as an additional genetic SIDS risk factor in children whose mothers smoke. (PMID:20198379)
• patient heterozygous for 4 FMO3 mutations (PMID:21075259)
• It was found that FMO3 158K, 257M and 308G alleles, demonstrate impaired metabolism toward many FMO3 substrates, were observed frequently in Turkish population similar to the other populations (PMID:22409263)
• Six novel variants of the FMO3 gene have been found responsible for trimethylaminuria in a Japanese population. (PMID:22819296)
• data support the role of FMO3 in the N-oxidation of OLA and implicate for the first time the contribution of FMO1 and its functional *6 variant in OLA disposition (PMID:23147717)
• Polymorphisms in FMO3 influence nicotine clearance and that these genetic variants in turn influence cigarette consumption. (PMID:23211429)
• Genetic variations in the FMO3 gene in patients with trimethylaminuria do not always present with fish-like body odor. (PMID:23266626)
• single-nucleotide polymorphisms in the FMO3 gene is associated with chronic allograft dysfunction. (PMID:23350966)
• FMO3 heterozygote genotypes increase the risk of stroke 6 times in hypertensives in Turkish population. (PMID:23510775)
• provides fundamental, up-to-date information on the importance of human FMO3 in individual xenobiotic oxygenations, including those of new medicines and dietary-derived trimethylamine (PMID:23567996)
• Novel variations in the FMO3 gene associated with trimethylaminuria. (PMID:23791655)
• CYP3A4 and FMO3 are the major enzymes responsible for the metabolism of teneligliptin in humans. (PMID:23855261)
• Comparisons of genotype and phenotype reveal that severe trimethylaminuria is caused by loss of function mutations in FMO3 (PMID:24028545)
• FMO3 (rs2266780) was in complete linkage disequilibrium with FMO6. (PMID:24173915)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fmo3	ENSMUSG00000026691
rattus_norvegicus	Fmo3	ENSRNOG00000003620
caenorhabditis_elegans		WBGENE00001476
caenorhabditis_elegans		WBGENE00001478
caenorhabditis_elegans		WBGENE00001480
caenorhabditis_elegans	C01H6.4	WBGENE00007254
caenorhabditis_elegans	C46H11.2	WBGENE00016728

Paralogs (5): FMO1 (ENSG00000010932), FMO4 (ENSG00000076258), FMO2 (ENSG00000094963), FOXRED2 (ENSG00000100350), FMO5 (ENSG00000131781)

Protein

Protein identifiers

Flavin-containing monooxygenase 3 — P31513 (reviewed: P31513)

Alternative names: Dimethylaniline monooxygenase [N-oxide-forming] 3, Dimethylaniline oxidase 3, FMO II, FMO form 2, Hepatic flavin-containing monooxygenase 3, Trimethylamine monooxygenase

All UniProt accessions (4): P31513, A0A024R8Z4, V9GYP3, V9GZ60

UniProt curated annotations — full annotation on UniProt →

Function. Essential hepatic enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including drugs as well as dietary compounds. Plays an important role in the metabolism of trimethylamine (TMA), via the production of trimethylamine N-oxide (TMAO) metabolite. TMA is generated by the action of gut microbiota using dietary precursors such as choline, choline containing compounds, betaine or L-carnitine. By regulating TMAO concentration, FMO3 directly impacts both platelet responsiveness and rate of thrombus formation.

Subcellular location. Microsome membrane. Endoplasmic reticulum membrane.

Tissue specificity. Liver.

Disease relevance. Trimethylaminuria (TMAU) [MIM:602079] Inborn error of metabolism associated with an offensive body odor and caused by deficiency of FMO-mediated N-oxidation of amino-trimethylamine (TMA) derived from foodstuffs. Affected individuals excrete relatively large amounts of TMA in their urine, sweat, and breath, and exhibit a fishy body odor characteristic of the malodorous free amine. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the FMO family.

RefSeq proteins (4): NP_001002294, NP_001306102, NP_001306103, NP_008825 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000960	Flavin_mOase	Family
IPR002255	Flavin_mOase_3	Family
IPR020946	Flavin_mOase-like	Family
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR050346	FMO-like	Family

Pfam: PF00743

Enzyme classification (BRENDA):

• EC 1.14.13.148 — trimethylamine monooxygenase (BRENDA: 19 organisms, 37 substrates, 22 inhibitors, 46 Km, 15 kcat entries)
• EC 1.14.13.8 — flavin-containing monooxygenase (BRENDA: 30 organisms, 458 substrates, 77 inhibitors, 260 Km, 123 kcat entries)

Substrate kinetics (BRENDA)

85 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
METHIMAZOLE	0.007–0.5758	18
TAMOXIFEN	0.0013–0.121	15
INDOLE	0.005–0.9	13
NADPH	0.0008–0.1348	11
BENZYDAMINE	0.0186–0.0659	11
ETHIONAMIDE	0.104–2.131	10
METHYL P-TOLYL SULFIDE	0.0048–10.2	10
FENTHION	0.145–0.351	9
MERCAPTOIMIDAZOLE	0.018–0.0527	9
NADPH	0.0031–0.132	9
TRIMETHYLAMINE	0.0015–0.58	9
N,N,N-TRIMETHYLAMINE	0.0003–0.139	8
SULINDAC SULFIDE	0.0101–0.0163	8
METHIMAZOLE	0.0282–0.116	7
CHLORPROMAZINE	0.022–0.08	7

Catalyzed reactions (Rhea), 5 shown:

• albendazole + NADPH + O2 + H(+) = albendazole S-oxide + NADP(+) + H2O (RHEA:10796)
• N,N-dimethylaniline + NADPH + O2 + H(+) = N,N-dimethylaniline N-oxide + NADP(+) + H2O (RHEA:24468)
• trimethylamine + NADPH + O2 = trimethylamine N-oxide + NADP(+) + H2O (RHEA:31979)
• (S)-nicotine + NADPH + O2 = trans-(S)-nicotine N(1’)-oxide + NADP(+) + H2O (RHEA:58720)
• hypotaurine + NADPH + O2 + H(+) = taurine + NADP(+) + H2O (RHEA:69819)

UniProt features (42 total): sequence variant 21, sequence conflict 11, binding site 6, initiator methionine 1, chain 1, transmembrane region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31513-F1	95.50	0.92

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 (6): 9–13; 32; 40–41; 60–61; 61–62; 195–198

Post-translational modifications (1): 401

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-217271	FMO oxidises nucleophiles
R-HSA-5579019	Defective FMO3 causes TMAU

MSigDB gene sets: 163 (showing top): MODULE_93, REACTOME_BIOLOGICAL_OXIDATIONS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, HSIAO_LIVER_SPECIFIC_GENES, FUJIWARA_PARK2_HEPATOCYTE_PROLIFERATION_DN, HP1SITEFACTOR_Q6, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, MODULE_88, CHIANG_LIVER_CANCER_SUBCLASS_PROLIFERATION_DN, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK

GO Biological Process (1): taurine biosynthetic process (GO:0042412)

GO Molecular Function (10): N,N-dimethylaniline monooxygenase activity (GO:0004499), trimethylamine monooxygenase activity (GO:0034899), albendazole monooxygenase activity (GO:0047638), hypotaurine monooxygenase activity (GO:0047822), flavin adenine dinucleotide binding (GO:0050660), NADP binding (GO:0050661), monooxygenase activity (GO:0004497), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen (GO:0016709)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), intracellular membrane-bounded organelle (GO:0043231), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Phase I - Functionalization of compounds	1
Metabolic disorders of biological oxidation enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen	4
taurine metabolic process	1
alkanesulfonate biosynthetic process	1
nucleotide binding	1
anion binding	1
adenyl nucleotide binding	1
oxidoreductase activity	1
binding	1
catalytic activity	1
monooxygenase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular anatomical structure	1
membrane-bounded organelle	1
intracellular organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1808 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FMO3	CYP3A4	P05184	703
FMO3	CYP2A6	P00190	694
FMO3	CYP1A2	P05177	672
FMO3	CYP2C19	P33259	667
FMO3	CYP2D6	P10635	644
FMO3	CYP2B6	P20813	641
FMO3	CUTC	Q9NTM9	632
FMO3	CYP2C8	P10632	621
FMO3	UGT1A4	P22310	616
FMO3	UGT1A6	P19224	571
FMO3	UGT1A1	P22309	564
FMO3	UGT1A10	Q9HAW8	564
FMO3	UGT1A9	P36509	556
FMO3	UGT1A7	Q9HAW7	556
FMO3	UGT1A8	Q9HAW9	556

IntAct

17 interactions, top by confidence:

A	B	Type	Score
FMO3	CREB3	psi-mi:“MI:0915”(physical association)	0.670
FMO3	SGSM3	psi-mi:“MI:0915”(physical association)	0.560
FMO3	SACM1L	psi-mi:“MI:0915”(physical association)	0.560
FMO3	CLEC10A	psi-mi:“MI:0915”(physical association)	0.560
FMO3	NRAS	psi-mi:“MI:0915”(physical association)	0.400
CREB3	FMO3	psi-mi:“MI:0915”(physical association)	0.370
	AP3B1	psi-mi:“MI:0914”(association)	0.350
FMO3	SGSM3	psi-mi:“MI:0915”(physical association)	0.000
SACM1L	FMO3	psi-mi:“MI:0915”(physical association)	0.000
FMO3	CLEC10A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): CREB3 (Two-hybrid), SGSM3 (Two-hybrid), CLEC10A (Two-hybrid), SACM1L (Two-hybrid), NRAS (Affinity Capture-MS)

ESM2 similar proteins: A0A0P0V5U9, B4F6I3, B5WWZ8, B5WWZ9, B8ANW0, F4IF99, M1BYJ7, O04196, O23024, O23617, O49312, O64489, O65709, O80596, O80738, O81815, O81816, P17636, P31512, P31513, P49328, P97501, Q06402, Q06429, Q0WUI9, Q10RE2, Q14534, Q6GLW8, Q7YS44, Q8HYJ9, Q8K4B7, Q8L7M0, Q8SPQ7, Q8VHG0, Q8VZ59, Q94AH8, Q94BP3, Q9FLC2, Q9FVQ0, Q9LFM5

Diamond homologs: A0A0E3D8M4, A0A0L1JEZ9, A0A140JWS7, A0A2I2F2K8, I1RF61, P0DXV5, P31513, P36367, P38866, P49109, P49328, Q7YS44, A3VVZ4, B8EIZ7, O60774, P16549, P17635, P17636, P31512, P32417, P36365, P36366, P49326, P50285, P97501, P97872, Q01740, Q04799, Q28505, Q2W0C9, Q5REK0, Q6IRI9, Q8HYJ9, Q8HZ69, Q8HZ70, Q8K2I3, Q8K4B7, Q8K4C0, Q8SPQ7, Q8VHG0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	44
Uncertain significance	73
Likely benign	93
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1322927	NM_001002294.3(FMO3):c.622G>T (p.Glu208Ter)	Pathogenic
16304	NM_001002294.3(FMO3):c.913G>T (p.Glu305Ter)	Pathogenic
16310	NM_001002294.3(FMO3):c.442G>T (p.Gly148Ter)	Pathogenic
16312	NM_001002294.3(FMO3):c.940G>T (p.Glu314Ter)	Pathogenic
16315	NG_012690.2:g.4664_16889del	Pathogenic
16317	NM_001002294.3(FMO3):c.192del (p.Glu65fs)	Pathogenic
2627164	NM_001002294.3(FMO3):c.1408C>T (p.Gln470Ter)	Pathogenic
2692638	NM_001002294.3(FMO3):c.1005C>A (p.Tyr335Ter)	Pathogenic
2694513	NM_001002294.3(FMO3):c.625C>T (p.Gln209Ter)	Pathogenic
2696531	NM_001002294.3(FMO3):c.16del (p.Ala6fs)	Pathogenic
2700823	NM_001002294.3(FMO3):c.674_690del (p.Trp225fs)	Pathogenic
2702541	NM_001002294.3(FMO3):c.1210del (p.Asp404fs)	Pathogenic
2706869	NM_001002294.3(FMO3):c.358_368del (p.Ala120fs)	Pathogenic
2708285	NM_001002294.3(FMO3):c.768_769insAGATGACTG (p.Val257delinsArgTer)	Pathogenic
2734029	NM_001002294.3(FMO3):c.209C>T (p.Pro70Leu)	Pathogenic
2734031	NM_001002294.3(FMO3):c.778A>G (p.Met260Val)	Pathogenic
2734032	NM_001002294.3(FMO3):c.1183+1del	Pathogenic
2734480	NM_001002294.3(FMO3):c.775C>T (p.Gln259Ter)	Pathogenic
2744460	NM_001002294.3(FMO3):c.170C>G (p.Ser57Ter)	Pathogenic
2764607	NM_001002294.3(FMO3):c.1257G>A (p.Trp419Ter)	Pathogenic
2766791	NM_001002294.3(FMO3):c.22_29del (p.Ile8fs)	Pathogenic
2770296	NM_001002294.3(FMO3):c.1231G>T (p.Glu411Ter)	Pathogenic
2829029	NM_001002294.3(FMO3):c.1237dup (p.Met413fs)	Pathogenic
2840209	NM_001002294.3(FMO3):c.174_175insA (p.Phe59fs)	Pathogenic
2840296	NM_001002294.3(FMO3):c.488_489del (p.Leu163fs)	Pathogenic
2852024	NM_001002294.3(FMO3):c.692G>A (p.Trp231Ter)	Pathogenic
2857220	NM_001002294.3(FMO3):c.102dup (p.Asn35fs)	Pathogenic
2863131	NM_001002294.3(FMO3):c.839_842dup (p.Pro282fs)	Pathogenic
2898902	NM_001002294.3(FMO3):c.1A>G (p.Met1Val)	Pathogenic
2993513	NM_001002294.3(FMO3):c.406G>T (p.Glu136Ter)	Pathogenic

SpliceAI

1316 predictions. Top by Δscore:

Variant	Effect	Δscore
1:171092786:TTTCA:T	donor_gain	1.0000
1:171092787:TTCA:T	donor_gain	1.0000
1:171092791:G:GG	donor_gain	1.0000
1:171116206:A:AG	acceptor_gain	1.0000
1:171116207:G:GG	acceptor_gain	1.0000
1:171092787:TTCAG:T	donor_loss	0.9900
1:171092788:TCA:T	donor_gain	0.9900
1:171092788:TCAG:T	donor_loss	0.9900
1:171092789:CA:C	donor_gain	0.9900
1:171092789:CAG:C	donor_loss	0.9900
1:171092790:AGTG:A	donor_loss	0.9900
1:171092791:GTGA:G	donor_loss	0.9900
1:171092792:TGA:T	donor_loss	0.9900
1:171092793:G:GG	donor_loss	0.9900
1:171092794:A:AC	donor_loss	0.9900
1:171092795:G:T	donor_loss	0.9900
1:171107674:GACAT:G	acceptor_gain	0.9900
1:171107713:A:AG	acceptor_gain	0.9900
1:171107714:A:G	acceptor_gain	0.9900
1:171107719:T:A	acceptor_gain	0.9900
1:171107833:TCCAG:T	donor_loss	0.9900
1:171107834:CCAG:C	donor_loss	0.9900
1:171107835:CAGG:C	donor_loss	0.9900
1:171107836:AGG:A	donor_loss	0.9900
1:171107837:GGT:G	donor_loss	0.9900
1:171107838:GT:G	donor_loss	0.9900
1:171107839:T:G	donor_loss	0.9900
1:171108073:A:AG	acceptor_gain	0.9900
1:171108074:CTCA:C	acceptor_loss	0.9900
1:171108077:A:AG	acceptor_gain	0.9900

AlphaMissense

3564 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:171092779:T:A	W41R	0.996
1:171092779:T:C	W41R	0.996
1:171107791:T:G	C146W	0.995
1:171107726:T:A	W125R	0.994
1:171107726:T:C	W125R	0.994
1:171092781:G:C	W41C	0.993
1:171092781:G:T	W41C	0.993
1:171103844:A:C	K64N	0.993
1:171103844:A:T	K64N	0.993
1:171108111:A:C	S173R	0.993
1:171108113:C:A	S173R	0.993
1:171108113:C:G	S173R	0.993
1:171114339:G:C	R387P	0.993
1:171092695:A:C	S13R	0.991
1:171092697:T:A	S13R	0.991
1:171092697:T:G	S13R	0.991
1:171092748:C:G	C30W	0.991
1:171108193:C:A	A200D	0.991
1:171110807:A:C	S213R	0.991
1:171110809:T:A	S213R	0.991
1:171110809:T:G	S213R	0.991
1:171108177:T:C	S195P	0.990
1:171110825:T:A	W219R	0.990
1:171110825:T:C	W219R	0.990
1:171092675:C:A	A6D	0.989
1:171107733:T:A	V127D	0.989
1:171108160:T:A	V189E	0.989
1:171108181:G:A	G196D	0.989
1:171107796:G:A	G148E	0.988
1:171108176:T:A	N194K	0.988

dbSNP variants (sampled 300 via entrez): RS1000037144 (1:171093758 T>G), RS1000101142 (1:171099560 C>A,G), RS1000147962 (1:171093553 A>G), RS1000270017 (1:171117478 C>A), RS1000299536 (1:171094907 C>T), RS1000301316 (1:171117878 T>A), RS1000416328 (1:171102697 G>A), RS1000499907 (1:171112654 G>C), RS1000594993 (1:171109046 G>T), RS1000642658 (1:171089214 A>C,G), RS1000829166 (1:171115183 T>A), RS1000858689 (1:171100576 A>G), RS1001287866 (1:171100265 G>A), RS1001482525 (1:171094085 T>C), RS1001522058 (1:171113082 G>A,C,T)

Disease associations

OMIM: gene MIM:136132 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
severe primary trimethylaminuria	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
trimethylaminuria	Definitive	AR

Mondo (2): trimethylaminuria (MONDO:0011182), severe primary trimethylaminuria (MONDO:0018767)

Orphanet (1): NON RARE IN EUROPE: Trimethylaminuria (Orphanet:35056)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000739	Anxiety
HP:0000822	Hypertension
HP:0001649	Tachycardia
HP:0001744	Splenomegaly
HP:0001875	Decreased total neutrophil count
HP:0001903	Anemia
HP:0003614	Trimethylaminuria
HP:0006532	Recurrent pneumonia
HP:0008770	Obsessive-compulsive trait
HP:0011999	Paranoia
HP:0031467	Dysregulated negative emotional state
HP:0031469	Low self-esteem
HP:0410020	Fish odor

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001640_3	Lentiform nucleus volume	5.000000e-08
GCST012020_240	Serum metabolite levels	3.000000e-21
GCST012020_36	Serum metabolite levels	2.000000e-15

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536561	Trimethylaminuria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3430864 (SINGLE PROTEIN), CHEMBL3542432 (PROTEIN FAMILY)

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

PharmGKB clinical annotations

8 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1736557	Efficacy	3	rosuvastatin
rs1736557	Toxicity	4	anthracyclines and related substances	Neoplasms
rs2266780	Other	3	olanzapine
rs2266780	Other	3	itopride
rs2266780	Metabolism/PK	3	sulindac
rs2266780	Metabolism/PK	3	nicotine	Tobacco Use Disorder
rs2266782	Other	3	itopride
rs2266782	Metabolism/PK	3	sulindac

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1736557	FMO3	3	2.75	2	anthracyclines and related substances;rosuvastatin
rs2266780	FMO3	3	4.25	4	olanzapine;nicotine;itopride;sulindac
rs2266782	FMO3	3	1.50	2	itopride;sulindac
rs1800822	FMO3		0.00	0
rs909530	FMO3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trimethylamine	affects metabolic processing, increases metabolic processing, increases oxidation	5
Benzydamine	increases chemical synthesis, affects metabolic processing, increases metabolic processing, increases oxidation, decreases reaction	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
Aflatoxin B1	decreases expression, decreases methylation	3
sulindac sulfide	increases metabolic processing, affects metabolic processing	2
clozapine N-oxide	decreases reaction, increases chemical synthesis, increases abundance	2
Acetaminophen	decreases response to substance, decreases expression	2
Clozapine	increases metabolic processing	2
Sulindac	increases response to substance, increases metabolic processing, affects metabolic processing, decreases metabolic processing	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
fluxapyroxad	decreases expression	1
imipramine N-oxide	increases abundance	1
lasiocarpine	decreases expression	1
alpha-naphthyl thiourea	increases response to substance	1
amitriptyline N-oxide	increases abundance	1
bisphenol A	increases expression, affects cotreatment	1
chlortoluron	decreases expression	1
potassium perchlorate	decreases expression	1
senkirkine	decreases expression	1
heliotrine	decreases expression	1
olivacine	affects metabolic processing	1
beta-lapachone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
azoxystrobin	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
methamphetamine hydroxylamine	increases abundance	1
almotriptan	increases oxidation	1
(+)-JQ1 compound	decreases expression	1
MT19c compound	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3529555	ADMET	Drug metabolism in insect microsomes assessed as FMO3 (unknown origin)-mediated nicotinamide N-oxide formation after 30 mins by HPLC analysis	Nicotinamide N-oxidation by CYP2E1 in human liver microsomes. — Drug Metab Dispos

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford