chr1-171107825-GAG-AAA

Variant names:

• chr1-171107825-GAG-AAA
• NM_001002294.3:c.472_474delinsAAA
• FMO3 p.Glu158Lys

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_001002294.3(FMO3):c.472_474delinsAAA (p.Glu158Lys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E158K: Benign/Likely_benign (ClinVar VariationId 38394, 2 stars); p.E158*: unknown significance (ClinVar VariationId 4322783) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FMO3 NM_001002294.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 0 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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.472_474delinsAAA p.Glu158Lys	missense	Exon 4 of 9	Prot: NP_001002294.1
	FMO3 NM_006894.6		c.472_474delinsAAA p.Glu158Lys	missense	Exon 4 of 9	Prot: NP_008825.4
	FMO3 NM_001319173.2		c.412_414delinsAAA p.Glu138Lys	missense	Exon 5 of 10	Prot: NP_001306102.1

FMO3 NM_001002294.3

MANE Select

HGVSc / HGVSpc.472_474delinsAAAp.Glu158Lys

Exon rankExon 4 of 9

missense

Prot: NP_001002294.1

FMO3 NM_006894.6

HGVSc / HGVSpc.472_474delinsAAAp.Glu158Lys

Exon rankExon 4 of 9

missense

Prot: NP_008825.4

FMO3 NM_001319173.2

HGVSc / HGVSpc.412_414delinsAAAp.Glu138Lys

Exon rankExon 5 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.472_474delinsAAA p.Glu158Lys	missense	Exon 4 of 9	Prot: ENSP00000356729
	FMO1-AS1 ENST00000669750.1		n.533+60277_533+60279delinsTTT	intronnon_coding_transcript	Intron 3 of 4	Prot:
	FMO3 ENST00000896149.1		c.472_474delinsAAA p.Glu158Lys	missense	Exon 4 of 9	Prot: ENSP00000566208

FMO3 ENST00000367755.9

MANE Select

HGVSc / HGVSpc.472_474delinsAAAp.Glu158Lys

Exon rankExon 4 of 9

missense

Prot: ENSP00000356729

FMO1-AS1 ENST00000669750.1

HGVSc / HGVSpn.533+60277_533+60279delinsTTT

Exon rankIntron 3 of 4

intronnon_coding_transcript

Prot:

FMO3 ENST00000896149.1

HGVSc / HGVSpc.472_474delinsAAAp.Glu158Lys

Exon rankExon 4 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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	1.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr1-171076966;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar