rs2266780

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001002294.3(FMO3):c.923A>G(p.Glu308Gly) variant causes a missense change. The variant allele was found at a frequency of 0.176 in 1,613,186 control chromosomes in the GnomAD database, including 27,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1936 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25663 hom. )

Consequence

FMO3
NM_001002294.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.31

Publications

129 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016511381).

BP6

Variant 1-171114102-A-G is Benign according to our data. Variant chr1-171114102-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3 link	c.923A>G	p.Glu308Gly	missense_variant	Exon 7 of 9	ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9 link	c.923A>G	p.Glu308Gly	missense_variant	Exon 7 of 9	1	NM_001002294.3	ENSP00000356729.4

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21104

AN:

152064

Hom.:

1936

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0415

Gnomad AMI

AF:

0.137

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.0501

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.120

GnomAD2 exomes

AF:

0.150

AC:

37773

AN:

251032

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.0370

Gnomad AMR exome

AF:

0.0888

Gnomad ASJ exome

AF:

0.117

Gnomad EAS exome

AF:

0.181

Gnomad FIN exome

AF:

0.238

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.180

AC:

262373

AN:

1461004

Hom.:

25663

Cov.:

AF XY:

0.176

AC XY:

127980

AN XY:

726782

show subpopulations

African (AFR)

AF:

0.0351

AC:

1175

AN:

33466

American (AMR)

AF:

0.0891

AC:

3983

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3101

AN:

26126

East Asian (EAS)

AF:

0.186

AC:

7372

AN:

39676

South Asian (SAS)

AF:

0.0519

AC:

4479

AN:

86248

European-Finnish (FIN)

AF:

0.243

AC:

12991

AN:

53408

Middle Eastern (MID)

AF:

0.0463

AC:

267

AN:

5764

European-Non Finnish (NFE)

AF:

0.198

AC:

219652

AN:

1111260

Other (OTH)

AF:

0.155

AC:

9353

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

10413

20826

31239

41652

52065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7474

14948

22422

29896

37370

<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:

0.139

AC:

21106

AN:

152182

Hom.:

1936

Cov.:

AF XY:

0.139

AC XY:

10329

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0414

AC:

1719

AN:

41540

American (AMR)

AF:

0.100

AC:

1532

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

407

AN:

3470

East Asian (EAS)

AF:

0.182

AC:

941

AN:

5162

South Asian (SAS)

AF:

0.0500

AC:

241

AN:

4822

European-Finnish (FIN)

AF:

0.236

AC:

2498

AN:

10580

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.197

AC:

13381

AN:

68000

Other (OTH)

AF:

0.120

AC:

253

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

895

1789

2684

3578

4473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<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:

0.168

Hom.:

10900

Bravo

AF:

0.124

TwinsUK

AF:

0.195

AC:

722

ALSPAC

AF:

0.193

AC:

742

ESP6500AA

AF:

0.0429

AC:

189

ESP6500EA

AF:

0.188

AC:

1619

ExAC

AF:

0.153

AC:

18539

Asia WGS

AF:

0.107

AC:

370

AN:

3478

EpiCase

AF:

0.167

EpiControl

AF:

0.171

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Trimethylaminuria

Benign:4

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 06, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32653296, 23510775, 31240165, 28290528, 19321370, 17531949, 10479479, 11773868, 23211429, 10896299, 23791655, 23266626, 17142560, 12814961, 17584019, 11136294)

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.3

PhyloP100

5.3

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.22

Sift

Benign

0.20

Sift4G

Benign

0.15

Vest4

0.032

ClinPred

0.035

GERP RS

3.6

Varity_R

0.42

gMVP

0.60

Mutation Taster

=56/44

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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