1-171108231-C-G

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.627+10C>G variant causes a intron change. The variant allele was found at a frequency of 0.217 in 1,613,030 control chromosomes in the GnomAD database, including 39,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3785 hom., cov: 31)

Exomes 𝑓: 0.22 ( 35776 hom. )

Consequence

FMO3
NM_001002294.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.32

Publications

19 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 (BayesDel_noAF=-0.79).

BP6

Variant 1-171108231-C-G is Benign according to our data. Variant chr1-171108231-C-G is described in ClinVar as Benign. ClinVar VariationId is 260076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3 link	c.627+10C>G		intron_variant	Intron 5 of 8	ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9 link	c.627+10C>G		intron_variant	Intron 5 of 8	1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1 link	c.573+10C>G		intron_variant	Intron 5 of 5	5		ENSP00000477451.1

Frequencies

GnomAD3 genomes

AF:

0.218

AC:

33130

AN:

151840

Hom.:

3779

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.0195

Gnomad SAS

AF:

0.280

Gnomad FIN

AF:

0.202

Gnomad MID

AF:

0.220

Gnomad NFE

AF:

0.220

Gnomad OTH

AF:

0.220

GnomAD2 exomes

AF:

0.210

AC:

52781

AN:

250764

AF XY:

0.215

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.202

Gnomad EAS exome

AF:

0.0202

Gnomad FIN exome

AF:

0.202

Gnomad NFE exome

AF:

0.220

Gnomad OTH exome

AF:

0.210

GnomAD4 exome

AF:

0.216

AC:

316311

AN:

1461074

Hom.:

35776

Cov.:

AF XY:

0.219

AC XY:

159394

AN XY:

726828

show subpopulations

African (AFR)

AF:

0.249

AC:

8330

AN:

33430

American (AMR)

AF:

0.205

AC:

9143

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

5322

AN:

26116

East Asian (EAS)

AF:

0.0170

AC:

674

AN:

39674

South Asian (SAS)

AF:

0.287

AC:

24764

AN:

86244

European-Finnish (FIN)

AF:

0.203

AC:

10845

AN:

53396

Middle Eastern (MID)

AF:

0.274

AC:

1576

AN:

5754

European-Non Finnish (NFE)

AF:

0.218

AC:

242612

AN:

1111444

Other (OTH)

AF:

0.216

AC:

13045

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

11777

23554

35331

47108

58885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8344

16688

25032

33376

41720

<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:

0.218

AC:

33155

AN:

151956

Hom.:

3785

Cov.:

AF XY:

0.216

AC XY:

16058

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.248

AC:

10255

AN:

41424

American (AMR)

AF:

0.202

AC:

3075

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

700

AN:

3470

East Asian (EAS)

AF:

0.0194

AC:

100

AN:

5164

South Asian (SAS)

AF:

0.280

AC:

1345

AN:

4808

European-Finnish (FIN)

AF:

0.202

AC:

2135

AN:

10556

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.220

AC:

14929

AN:

67972

Other (OTH)

AF:

0.218

AC:

458

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1278

2556

3834

5112

6390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.170

Hom.:

523

Bravo

AF:

0.219

Asia WGS

AF:

0.127

AC:

446

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Trimethylaminuria

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.24

PhyloP100

4.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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