rs1736557

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001002294.3(FMO3):c.769G>A(p.Val257Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,613,770 control chromosomes in the GnomAD database, including 5,296 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 407 hom., cov: 32)

Exomes 𝑓: 0.076 ( 4889 hom. )

Consequence

FMO3
NM_001002294.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: -1.35

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 links:

ENSG00000231424 (HGNC:40240):

ENSG00000231424 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024797022).

BP6

Variant 1-171110939-G-A is Benign according to our data. Variant chr1-171110939-G-A is described in ClinVar as [Benign]. Clinvar id is 16305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-171110939-G-A is described in Lovd as [Benign]. Variant chr1-171110939-G-A is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3 link	c.769G>A	p.Val257Met	missense_variant	Exon 6 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.769G>A	p.Val257Met	missense_variant	Exon 6 of 9	1	NM_001002294.3	ENSP00000356729.4		P31513
FMO3	ENST00000479749.1 link	c.*61G>A		downstream_gene_variant		5		ENSP00000477451.1		V9GZ60

Frequencies

GnomAD3 genomes

AF:

0.0654

AC:

9948

AN:

152106

Hom.:

405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0365

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0803

Gnomad ASJ

AF:

0.114

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0692

Gnomad OTH

AF:

0.0703

GnomAD3 exomes

AF:

0.0815

AC:

20473

AN:

251052

Hom.:

1103

AF XY:

0.0819

AC XY:

11107

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.0359

Gnomad AMR exome

AF:

0.0871

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.201

Gnomad SAS exome

AF:

0.0941

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0691

Gnomad OTH exome

AF:

0.0772

GnomAD4 exome

AF:

0.0758

AC:

110765

AN:

1461546

Hom.:

4889

Cov.:

AF XY:

0.0760

AC XY:

55230

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0350

Gnomad4 AMR exome

AF:

0.0865

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.185

Gnomad4 SAS exome

AF:

0.0929

Gnomad4 FIN exome

AF:

0.0439

Gnomad4 NFE exome

AF:

0.0721

Gnomad4 OTH exome

AF:

0.0744

GnomAD4 genome

AF:

0.0654

AC:

9958

AN:

152224

Hom.:

407

Cov.:

AF XY:

0.0662

AC XY:

4930

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0365

Gnomad4 AMR

AF:

0.0811

Gnomad4 ASJ

AF:

0.114

Gnomad4 EAS

AF:

0.186

Gnomad4 SAS

AF:

0.107

Gnomad4 FIN

AF:

0.0386

Gnomad4 NFE

AF:

0.0693

Gnomad4 OTH

AF:

0.0696

Alfa

AF:

0.0732

Hom.:

1196

Bravo

AF:

0.0659

TwinsUK

AF:

0.0750

AC:

278

ALSPAC

AF:

0.0714

AC:

275

ESP6500AA

AF:

0.0372

AC:

164

ESP6500EA

AF:

0.0693

AC:

596

ExAC

AF:

0.0805

AC:

9773

Asia WGS

AF:

0.136

AC:

472

AN:

3478

EpiCase

AF:

0.0702

EpiControl

AF:

0.0688

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Trimethylaminuria

Pathogenic:1Benign:2

Apr 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 06, 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. -

Mar 26, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FMO3 c.769G>A (p.Val257Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.082 in 251052 control chromosomes in the gnomAD database, including 1103 homozygotes. The observed variant frequency is approximately 14.59 fold of the estimated maximal expected allele frequency for a pathogenic variant in FMO3 causing Trimethylaminuria phenotype (0.0056), which is stand-alone evidence that the variant is benign. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed the variant had no effect on enzyme activity (Stormer_2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic (OMIM), and one laboratory classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.97

DANN

Benign

0.87

DEOGEN2

Benign

0.0072

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.052

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.59

PrimateAI

Benign

0.25

PROVEAN

Benign

0.030

REVEL

Benign

0.049

Sift

Benign

0.075

Sift4G

Benign

0.063

Polyphen

0.0020

Vest4

0.0050

MPC

0.045

ClinPred

0.0062

GERP RS

-9.2

Varity_R

0.042

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over