rs2266780

Variant names:

• chr1-171114102-A-G
• rs2266780
• NM_001002294.3:c.923A>G
• FMO3 p.Glu308Gly

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). O4_SupportingB1_StrongB3_Supporting

The NM_001002294.3(FMO3):c.923A>G (p.Glu308Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.176 (AC=283,479) in the gnomAD database across 1,613,186 control chromosomes, including 27,599 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.197. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant has been observed in cBioPortal in 6 samples across 5 studies and 5 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1936 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25663 hom.)
• Consequence: FMO3 NM_001002294.3 missense
• Predictors: REVEL: 0.22: Benign
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.31
• Publications: 140 publications found

Genes affected

FMO3 (HGNC:3771): (flavin containing dimethylaniline monoxygenase 3) 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]

FMO3 Gene-Disease associations (from GenCC):

• trimethylaminuria

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• severe primary trimethylaminuria

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)

FMO1-AS1 (HGNC:40240): ()

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=6 | studies=5 | cancer types=5 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.197 — exceeds 1% threshold (B1 applied)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001002294.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FMO3 NM_001002294.3	MANE Select	c.923A>G p.Glu308Gly	missense	Exon 7 of 9	Prot: NP_001002294.1
	FMO3 NM_006894.6		c.923A>G p.Glu308Gly	missense	Exon 7 of 9	Prot: NP_008825.4
	FMO3 NM_001319173.2		c.863A>G p.Glu288Gly	missense	Exon 8 of 10	Prot: NP_001306102.1

FMO3 NM_001002294.3

MANE Select

HGVSc / HGVSpc.923A>Gp.Glu308Gly

Exon rankExon 7 of 9

missense

Prot: NP_001002294.1

FMO3 NM_006894.6

HGVSc / HGVSpc.923A>Gp.Glu308Gly

Exon rankExon 7 of 9

missense

Prot: NP_008825.4

FMO3 NM_001319173.2

HGVSc / HGVSpc.863A>Gp.Glu288Gly

Exon rankExon 8 of 10

missense

Prot: NP_001306102.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FMO3 ENST00000367755.9	MANE Select	c.923A>G p.Glu308Gly	missense	Exon 7 of 9	Prot: ENSP00000356729
	FMO1-AS1 ENST00000669750.1		n.533+54002T>C	intronnon_coding_transcript	Intron 3 of 4	Prot:
	FMO3 ENST00000896149.1		c.923A>G p.Glu308Gly	missense	Exon 7 of 9	Prot: ENSP00000566208

FMO3 ENST00000367755.9

MANE Select

HGVSc / HGVSpc.923A>Gp.Glu308Gly

Exon rankExon 7 of 9

missense

Prot: ENSP00000356729

FMO1-AS1 ENST00000669750.1

HGVSc / HGVSpn.533+54002T>C

Exon rankIntron 3 of 4

intronnon_coding_transcript

Prot:

FMO3 ENST00000896149.1

HGVSc / HGVSpc.923A>Gp.Glu308Gly

Exon rankExon 7 of 9

missense

Prot: ENSP00000566208

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.139	AC:21104	Hom:1936	AN:152064	Cov:32
GnomAD2 exomes	AF: 0.150	AC:37773	Hom:	AN:251032	Cov:
GnomAD4 exome	AF: 0.180	AC:262373	Hom:25663	AN:1461004	Cov:33
GnomAD4 genome	AF: 0.139	AC:21106	Hom:1936	AN:152182	Cov:32
TOPMed (Bravo)	AF: 0.124	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.167	AC:122291	Hom:11256	AN:733376	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.110	AC:258	Hom:15	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.175	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.227	AC:68	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.139	AC:1808	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.107	AC:370	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.172	AC:1241	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0403	AC:81	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.197	AC:24196	Hom:2439	AN:122760	Cov:
Turkish Variome	AF: 0.0705	AC:474	Hom:23	AN:6724	Cov:
UK10K	AF: 0.194	AC:1464	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.180	AC:1609	Hom:166	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.237 *	2628	11090	0.234 *	4116	17608
BipEx(Bipolar disorder (including schizoaffective))	0.208	5909	28412	0.210	6043	28832
Epi25(Epilepsy)	0.167	7010	41946	0.160	10676	66878
SCHEMA(Schizophrenia)	0.167	21005	125454	0.174	37262	213722

Showing 4 cohortsAllele count / allele number. *AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Trimethylaminuria (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.81	D
GPN-Star LLR	N/A	-4.7
GPN-Star score	N/A	4.7
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.81	T
Mutation Taster	N/A	56/44	polymorphism (auto)
MutationAssessor	Benign	1.3	L
PhyloP100	Uncertain	5.3
popEVE	Benign	-3.2
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.22
Sift	Benign	0.20	T
Sift4G	Benign	0.15	T
Varity_R	N/A	0.42
VESM-3B	Benign	-8.2

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2266780;

hg19: chr1-171083242;

COSMIC: COSV63006935;

COSMIC: COSV63006935;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar