rs1736557

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

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:5

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]

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
FMO3NM_001002294.3 linkc.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
FMO3ENST00000367755.9 linkc.769G>A p.Val257Met missense_variant Exon 6 of 9 1 NM_001002294.3 ENSP00000356729.4 P31513
FMO3ENST00000479749.1 linkc.*61G>A downstream_gene_variant 5 ENSP00000477451.1 V9GZ60

Frequencies

GnomAD3 genomes
AF:
0.0654
AC:
9948
AN:
152106
Hom.:
405
Cov.:
32
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.:
32
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.:
32
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:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Trimethylaminuria Pathogenic:1Benign:1
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
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. -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
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 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
0.077
BayesDel_addAF
Benign
-0.70
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
0.97
DANN
Benign
0.87
DEOGEN2
Benign
0.0072
T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.052
T
MetaRNN
Benign
0.0025
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.59
N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
0.030
N
REVEL
Benign
0.049
Sift
Benign
0.075
T
Sift4G
Benign
0.063
T
Polyphen
0.0020
B
Vest4
0.0050
MPC
0.045
ClinPred
0.0062
T
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.

Other links and lift over

dbSNP: rs1736557; hg19: chr1-171080080; COSMIC: COSV63006750; COSMIC: COSV63006750; API