FMO5

Chr 1

flavin containing dimethylaniline monoxygenase 5

Also known as: hBVMO1

NCBI Gene: 2330 ENSG00000131781 UniProt: P49326 OMIM: 603957

The FMO5 protein functions as a Baeyer-Villiger monooxygenase that catalyzes oxygen insertion into carbon-carbon bonds adjacent to carbonyls, converting ketones to esters, and also modulates cholesterol biosynthesis and glucose homeostasis. While other flavin-containing monooxygenases cause trimethylaminuria when mutated, no specific genetic disorders have been definitively associated with FMO5 mutations despite its metabolic functions. The gene shows high tolerance to loss-of-function variants (LOEUF 1.448), suggesting that complete loss of FMO5 function may be well-tolerated in humans.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Metabolic N-oxidation of the diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man resulting in a small subpopulation with reduced TMA N-oxidation capacity resulting in fish odor syndrome Trimethylaminuria. Three forms of the enzyme, FMO1 found in fetal liver, FMO2 found in adult liver, and FMO3 are encoded by genes clustered in the 1q23-q25 region. Flavin-containing monooxygenases are NADPH-dependent flavoenzymes that catalyzes the oxidation of soft nucleophilic heteroatom centers in drugs, pesticides, and xenobiotics. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.45

Clinical Summary— FMO5

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Gene-Disease Validity (ClinGen)

congenital heart disease · ADDisputed

Disputed — evidence questions this relationship

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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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ClinVar Variants

87 VUS of 108 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FMO5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.45LOEUF

pLI 0.000

Z-score -0.06

OE 1.01 (0.72–1.45)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.63Z-score

OE missense 1.10 (1.01–1.21)

319 obs / 288.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.01 (0.72–1.45)

0≤0.351.4

Missense OE?1.10 (1.01–1.21)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 22 / 21.7Missense obs/exp: 319 / 288.7Syn Z: 0.73

This gene — mechanism propensity

0.73top 25%

GOF

0.72top 25%

LOF

0.2776th %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.

ClinVar Variant Classifications

108 submitted variants in ClinVar

ClinVar

Classification Summary

VUS87

Likely Benign7

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	87	0	0	87
Likely Benign	4	1	2	7
Benign	0	0	1	1
Total	91	1	3	95

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

288 pathogenic / likely-pathogenic (of 302) ClinVar copy-number / structural variants overlap FMO5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →