FMO3

protein-coding

flavin containing dimethylaniline monoxygenase 3, the group of Flavin containing monooxygenases|MicroRNA protein coding host genes

Gene summary

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]

MANE transcript

NM_001002294.3

Inheritance

ClinVar variants

P:132U:76B:75

Top phenotype

Trimethylaminuria

gnomAD constraint

pLI —, LoF o/e 1.11

Max pathogenic AF

—

Genomic locus

chr1:171,090,901-171,117,819

External References & Databases

Ensembl (ENSG00000007933)

Transcript & Mutation Effects

hg38 • Region Span ~26.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

trimethylaminuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011182

Submitter: ClinGen

The relationship between FMO3 and trimethylaminuria, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 23, 2020. Primary trimethylaminuria is characterized by an unpleasant fishy body odor, similar to that of rotten fish, which results from increased excretion of trimethylamine in the urine, sweat, saliva, and reproductive fluids. Affected individuals appear healthy, with no physical symptoms, but the odor often results in social and psychological issues (GeneReviews, Philips and Shepard, 2015, PMID 20301282). Metabolism of trimethylamine is primarily via N-oxygenation in the liver, catalyzed by flavin-containing monooxygenase 3 (FMO3), which converts it to the non-odorous trimethylamine N-oxide. Trimethylamine is derived from the dietary, via the action of gut bacteria. Severe reduction in the activity of TMO3, caused by rare, deleterious variants in the FMO3 gene, is associated with primary trimethylaminuria. More common FMO3 variants, such as p.[(Glu158Lys);(Glu308Gly)], can moderately affect activity of FMO3 and may cause mild or transient trimethylaminuria (reviewed in Philips and Shepard, 2020, PMID 31317802). The relationship between FMO3 and trimethylaminuria is supported by case-level and experimental evidence. Biallelic variants in FMO3 were first reported in a patient with trimethylaminuria in 1997 (Dolphin et al, PMID 9398858). More than 40 variants have been reported to be associated with trimethylaminuria (FMO3 database, https://databases.lovd.nl/shared/variants/FMO3/unique, PMID 12938085; Philips and Shepard, 2020, PMID 31317802). Fourteen unique variants (missense, frameshift, and nonsense) in 10 probands from 5 publications were curated (Dolphin et al, 1997, PMID 9398858; Akerman et al, 1999, PMID 10479479; Teresa et al, 2006, PMID 16600650; Treacy et al, 2008, PMID 9536088; Shimizu et al, 2015, PMID 28649550). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Experimental evidence supporting this gene-disease relationship includes the biochemical function of FMO3, which is consistent with the biochemical findings in patients (Lang et al, 1998, PMID 9776311; Cashman et al, 1995, PMID, 7720103; reviewed in Philips and Shepard, 2020, PMID 31317802), and fishy-tasting milk and eggs, in cows and hens respectively, homozygous for FMO3 variants (Lundén et al, 2002, PMID 12466292; Honkatukia et al, 2005, PMID 15916878). In summary, FMO3 is definitively associated with trimethylaminuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.

severe primary trimethylaminuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018767

Submitter: Orphanet

severe primary trimethylaminuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018767

Submitter: PanelApp Australia

severe primary trimethylaminuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018767

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

TrimethylaminuriaAR

Manifestation: Biochemical

Intervention: Biochemical

Rationale: Treatment may involve dietary modification (eg, to restrict trimethylamine precursors), and medical/dietary treatment (eg, with agents such as metronidazole, neomycin, lactulose, copper chlorphyllin, or activated charcoal) as well as riboflavin supplementation (the use of specific pH soaps may be beneficial as well)

Refs: 7474897; 9398858; 9846928; 10646019; 10485731; 12653714; 12893987; 12938085; 15565078; 16601883; 22126753

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FMO3 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 186

TrimethylaminuriaTotal: 145

Inborn genetic diseasesTotal: 50

not specifiedTotal: 27

FMO3-related disorderTotal: 17

FMO3-related disordersTotal: 10

See casesTotal: 2

Type 2 diabetes mellitusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001002294.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	55 clinvar	2 clinvar	59
missense	2 clinvar	31 clinvar	70 clinvar	17 clinvar	1 clinvar	121
nonsense	28 clinvar	12 clinvar	1 clinvar			41
start loss	1 clinvar	1 clinvar				2
frameshift	29 clinvar	15 clinvar	2 clinvar			46
splice donor/acceptor (+/-2bp)		13 clinvar	1 clinvar			14
Total	60	72	76	72	3	283

Highest pathogenic variant AF is 0.0023689547

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001002294.3	RefSeq	NP_001002294.1	8	MANE Select
ENST00000367755.9	Ensembl	ENSP00000356729.4	8	MANE Select
NM_001319173.2	RefSeq	NP_001306102.1	8	Standard
NM_001319174.2	RefSeq	NP_001306103.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Drug metabolism - cytochrome P450 - Homo sapiens (human)
Busulfan Pathway, Pharmacodynamics
Tamoxifen Pathway, Pharmacokinetics
Nicotine Pathway, Pharmacokinetics
Nicotine Metabolism Pathway

Biological Process

xenobiotic metabolic process
oxidation-reduction process

Molecular Function

monooxygenase activity
N,N-dimethylaniline monooxygenase activity
protein binding
trimethylamine monooxygenase activity
flavin adenine dinucleotide binding

Cellular Component

endoplasmic reticulum membrane
integral component of membrane
organelle membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367755
Coding exons: 8
Length: 26942
Individuals with no LoFs: 125507
Homozygous LoFs: 0
Heterozygous LoFs: 236
Defined: 125743
p: 0.000939

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.163	300	292	1.03	0.0000147	3545
Missense (PolyPhen)		110	97.601	1.127		1284
Synonymous	1.08	92	106	0.867	0.00000562	991
Loss of Function	-0.464	22	19.8	1.11	9.08e-7	248

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0029	0.0029	notable
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00090	0.00090	rare
South Asian	0.0014	0.0014	notable
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an important role in the metabolism of trimethylamine (TMA), via the production of TMA N-oxide (TMAO). Is also able to perform S-oxidation when acting on sulfide compounds (PubMed:9224773). {ECO:0000250|UniProtKB:P97501, ECO:0000269|PubMed:9224773}.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.997
RVIS EVS: 1.04
RVIS percentile EVS: 91.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.178

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High