FMO3 p.Glu158Lys

Variant names:

• chr1-171107825-G-A
• rs2266782
• NM_001002294.3:c.472G>A
• FMO3 p.Glu158Lys

Your query was ambiguous. Multiple possible variants found:

• chr1-171107825-G-A
• chr1-171107825-GAG-AAA

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

The NM_001002294.3(FMO3):c.472G>A (p.Glu158Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.402 (AC=648,205) in the gnomAD database across 1,613,236 control chromosomes, including 133,065 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.457. 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 (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E158*: unknown significance (ClinVar VariationId 4322783) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.41 (12999 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120066 hom.)
• Consequence: FMO3 NM_001002294.3 missense
• Predictors: REVEL: 0.10: Benign
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.221
• Publications: 179 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (12/12 total B/LB).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4572 — exceeds 5%% threshold (BA1 applied)

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

FMO3 NM_001002294.3

MANE Select

HGVSc / HGVSpc.472G>Ap.Glu158Lys

Exon rankExon 4 of 9

missense

Prot: NP_001002294.1

FMO3 NM_006894.6

HGVSc / HGVSpc.472G>Ap.Glu158Lys

Exon rankExon 4 of 9

missense

Prot: NP_008825.4

FMO3 NM_001319173.2

HGVSc / HGVSpc.412G>Ap.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.472G>A p.Glu158Lys	missense	Exon 4 of 9	Prot: ENSP00000356729
	FMO1-AS1 ENST00000669750.1		n.533+60279C>T	intronnon_coding_transcript	Intron 3 of 4	Prot:
	FMO3 ENST00000896149.1		c.472G>A p.Glu158Lys	missense	Exon 4 of 9	Prot: ENSP00000566208

FMO3 ENST00000367755.9

MANE Select

HGVSc / HGVSpc.472G>Ap.Glu158Lys

Exon rankExon 4 of 9

missense

Prot: ENSP00000356729

FMO1-AS1 ENST00000669750.1

HGVSc / HGVSpn.533+60279C>T

Exon rankIntron 3 of 4

intronnon_coding_transcript

Prot:

FMO3 ENST00000896149.1

HGVSc / HGVSpc.472G>Ap.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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.407	AC:61759	Hom:12984	AN:151854	Cov:32
GnomAD2 exomes	AF: 0.374	AC:93922	Hom:	AN:251054	Cov:
GnomAD4 exome	AF: 0.401	AC:586405	Hom:120066	AN:1461262	Cov:43
GnomAD4 genome	AF: 0.407	AC:61800	Hom:12999	AN:151974	Cov:32
TOPMed (Bravo)	AF: 0.400	AC:105887	Hom:21866	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.405	AC:329664	Hom:68105	AN:813654	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.356	AC:834	Hom:154	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.200	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.467	AC:140	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.429	AC:5580	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.243	AC:847	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.195	AC:1409	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.294	AC:592	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.210	AC:25729	Hom:2761	AN:122776	Cov:
Turkish Variome	AF: 0.363	AC:2443	Hom:474	AN:6724	Cov:
UK10K	AF: 0.413	AC:3121	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.205	AC:1836	Hom:207	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.456 *	5066	11100	0.450 *	7928	17608
BipEx(Bipolar disorder (including schizoaffective))	0.425	12083	28418	0.431	12444	28844
Epi25(Epilepsy)	0.394	16529	41958	0.396	26478	66872
SCHEMA(Schizophrenia)	0.393	58482	148926	0.404	98873	244734

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
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	3	Trimethylaminuria (3)
-	-	1	See cases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.32	N
GPN-Star LLR	N/A	-5.2
GPN-Star score	N/A	5.2
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.00078	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	98/2	polymorphism (auto)
MutationAssessor	Benign	1.2	L
PhyloP100	Benign	0.22
popEVE	Benign	-2.9
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.56	T
Sift4G	Benign	0.47	T
Varity_R	N/A	0.13
VESM-3B	Benign	-6.0

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	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: rs2266782;

hg19: chr1-171076966;

COSMIC: COSV63006313;

COSMIC: COSV63006313;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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