rs72549331

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM5PP5BP4

The NM_001002294.3(FMO3):c.1160G>A(p.Arg387His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R387L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

FMO3
NM_001002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.52

Publications

13 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae)

FMO3 links:

ENSG00000231424 (HGNC:40240):

ENSG00000231424 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-171114339-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16311.

PP5

Variant 1-171114339-G-A is Pathogenic according to our data. Variant chr1-171114339-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 427174.

BP4

Computational evidence support a benign effect (MetaRNN=0.4070087). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3 link	c.1160G>A	p.Arg387His	missense_variant	Exon 7 of 9	ENST00000367755.9	NP_001002294.1	P31513A0A024R8Z4Q53FW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9 link	c.1160G>A	p.Arg387His	missense_variant	Exon 7 of 9	1	NM_001002294.3	ENSP00000356729.4		P31513

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000110

AC:

AN:

246470

AF XY:

0.0000971

show subpopulations

Gnomad AFR exome

AF:

0.0000640

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000364

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1460994

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33458

American (AMR)

AF:

0.0000448

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26122

East Asian (EAS)

AF:

0.000328

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111458

Other (OTH)

AF:

0.0000332

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000530

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Oct 09, 2017

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R387H variant in the FMO3 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different missense substitution at this residue (R387L) has been reported in the homozygous state in an individual with trimethylaminuria (Akerman et al., 1999). Although not present in the homozygous state, the R387H variant is observed in 21/18784 (0.11%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016). The R387H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R387H as a likely pathogenic variant. -

Trimethylaminuria

Pathogenic:1

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jun 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FMO3 c.1160G>A (p.Arg387His) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00011 in 246470 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FMO3 causing Trimethylaminuria (0.00011 vs 0.0056), allowing no conclusion about variant significance. c.1160G>A has been observed in individual(s) affected with Trimethylaminuria (example: Kilic_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Trimethylaminuria. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 50% of normal activity (Makiguchi_2023). The following publications have been ascertained in the context of this evaluation (PMID: 29745129, 37041084). ClinVar contains an entry for this variant (Variation ID: 427174). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.00069

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.063

MetaRNN

Benign

0.41

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.2

PhyloP100

7.5

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.53

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0060

Polyphen

0.97

Vest4

0.78

MVP

0.73

MPC

0.088

ClinPred

0.88

GERP RS

3.0

Varity_R

0.78

gMVP

0.86

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over