NM_001002294.3:c.172G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP5BP4BS1_Supporting

The NM_001002294.3(FMO3):c.172G>A(p.Val58Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

FMO3
NM_001002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 1.26

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001002294.3

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-171103824-G-A is Pathogenic according to our data. Variant chr1-171103824-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225365.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}. Variant chr1-171103824-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.009486079). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00023 (35/152206) while in subpopulation EAS AF= 0.00504 (26/5160). AF 95% confidence interval is 0.00353. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3 link	c.172G>A	p.Val58Ile	missense_variant	Exon 3 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.172G>A	p.Val58Ile	missense_variant	Exon 3 of 9	1	NM_001002294.3	ENSP00000356729.4		P31513
FMO3	ENST00000479749.1 link	c.172G>A	p.Val58Ile	missense_variant	Exon 3 of 6	5		ENSP00000477451.1		V9GZ60

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00503

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251230

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00419

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

186

AN:

1461688

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00333

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000230

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00504

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000305

Hom.:

Bravo

AF:

0.000242

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Trimethylaminuria

Pathogenic:1Uncertain:2

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.037%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest no damaging effect of the variant on gene or gene product [REVEL: 0.27 (<0.4); 3Cnet: 0.05 (<0.15, specificity 0.78 and negative predicitive value 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with FMO3 related disorder (ClinVar ID: VCV000225365 /PMID: 15618671). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

not provided

Pathogenic:1

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 58 of the FMO3 protein (p.Val58Ile). This variant is present in population databases (rs144935285, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of trimethylaminuria (PMID: 15618671, 22819296, 28392825, 33831674). This variant is also known as p.Val158Ile, G265A. ClinVar contains an entry for this variant (Variation ID: 225365). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FMO3 protein function. Experimental studies have shown that this missense change affects FMO3 function (PMID: 15618671, 22819296). For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Feb 13, 2024

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.172G>A (p.Val58Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251230 control chromosomes, predominantly at a frequency of 0.0042 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in FMO3 causing Trimethylaminuria (0.00035 vs 0.0056), allowing no conclusion about variant significance. c.172G>A has been reported in the literature in individuals affected with Trimethylaminuria (Kim_2017, Shimizu_2021, Shimizu_2012, Kubota_2002). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function indicating changes in protein function (Shimizu_2012, Kubota_2002) . The following publications have been ascertained in the context of this evaluation (PMID: 28392825, 15618671, 33831674, 22819296). ClinVar contains an entry for this variant (Variation ID: 225365). 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

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

T;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.0095

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Pathogenic

3.3

M;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.60

N;.

REVEL

Benign

0.27

Sift

Uncertain

0.022

D;.

Sift4G

Benign

0.11

T;T

Polyphen

0.50

P;.

Vest4

0.69

MVP

0.47

MPC

0.21

ClinPred

0.27

GERP RS

3.7

Varity_R

0.11

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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