FMO3

Chr 1AR

flavin containing dimethylaniline monoxygenase 3

Also known as: FMOII, TMAU, dJ127D3.1

NCBI Gene: 2328 ENSG00000007933 UniProt: P31513 OMIM: 136132

FMO3 encodes a hepatic enzyme that catalyzes the oxygenation of nitrogen- and sulfur-containing compounds including drugs and dietary compounds, and plays a crucial role in converting trimethylamine to trimethylamine N-oxide. Mutations cause trimethylaminuria, an autosomal recessive disorder characterized by accumulation and excretion of unmetabolized trimethylamine resulting in a distinctive body odor. The gene shows low constraint to loss-of-function variation (high LOEUF score of 1.58), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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.[provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.581 OMIM phenotype

Clinical Summary— FMO3

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Gene-Disease Validity (ClinGen)

trimethylaminuria · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.58LOEUF

pLI 0.000

Z-score -0.46

OE 1.11 (0.79–1.58)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.16Z-score

OE missense 1.03 (0.93–1.13)

300 obs / 292.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.11 (0.79–1.58)

0≤0.351.4

Missense OE?1.03 (0.93–1.13)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 22 / 19.8Missense obs/exp: 300 / 292.1Syn Z: 1.08

This gene — mechanism propensity

0.6938th %ile

GOF

0.6735th %ile

LOF

0.3066th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.