rs72549326

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP3PP5BP4BS1_SupportingBS2

The NM_001002294.3(FMO3):c.458C>T(p.Pro153Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,792 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 3 hom. )

Consequence

FMO3
NM_001002294.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1O:1

Conservation

PhyloP100: 7.85

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 Likely_benign. Variant got -4 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

PP5

Variant 1-171107811-C-T is Pathogenic according to our data. Variant chr1-171107811-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16308.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=5, not_provided=1}. Variant chr1-171107811-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.15120038). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00247 (3608/1461688) while in subpopulation NFE AF= 0.00313 (3484/1111896). AF 95% confidence interval is 0.00305. There are 3 homozygotes in gnomad4_exome. There are 1669 alleles in male gnomad4_exome 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

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3 link	c.458C>T	p.Pro153Leu	missense_variant	Exon 4 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.458C>T	p.Pro153Leu	missense_variant	Exon 4 of 9	1	NM_001002294.3	ENSP00000356729.4		P31513
FMO3	ENST00000479749.1 link	c.458C>T	p.Pro153Leu	missense_variant	Exon 4 of 6	5		ENSP00000477451.1		V9GZ60

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

215

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00102

AC:

256

AN:

251080

Hom.:

AF XY:

0.00101

AC XY:

137

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00247

AC:

3608

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

1669

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00313

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00141

AC:

215

AN:

152104

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.000604

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00198

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00219

Hom.:

Bravo

AF:

0.00168

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.000988

AC:

120

EpiCase

AF:

0.00262

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Trimethylaminuria

Pathogenic:4Other:1

Dec 08, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FMO3 c.458C>T (p.Pro153Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 251080 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FMO3 causing Trimethylaminuria (0.001 vs 0.0056), allowing no conclusion about variant significance. c.458C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Trimethylaminuria (e.g., Dolphin_1997, Treacy_1998), and the variant has been shown to segregate with disease in related individuals (e.g., Dolphin_1997). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in undetectable or severely reduced (<10%) enzymatic activity relative to the wild type (e.g., Dolphin_1997, Treacy_1998, Yeung_2007). The following publications have been ascertained in the context of this evaluation (PMID: 9398858, 9536088, 17531949). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 3; VUS, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 06, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FMO3 c.458C>T (p.Pro153Leu) missense variant is reported widely reported in the literature and is noted to be one of the most common variants in the FMO3 gene associated with disease (Philips et al. 2015). Across a selection of the available literature, the p.Pro153Leu variant was identified in a total of 14 individuals with trimethylaminuria, including eight homozygotes and six compound heterozygotes. Four unaffected family members were identified as heterozygotes for the p.Pro153Leu variant (Dolphin et al. 1997; Treacy et al. 1998; Dolphin et al. 2000; Chalmers et al. 2006). The variant was found in one of 108 control chromosomes, and is reported at a frequency of 0.00337 in the European American population of the Exome Sequencing Project. Functional analysis by several groups demonstrated that the p.Pro153Leu variant abolishes the catalytic activity of FMO3 (Dolphin et al. 1997; Cashman et al. 1997; Treacy et al. 1998). Based on the collective evidence, the p.Pro153Leu variant is classified as pathogenic for trimethylaminuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2Uncertain:1

Mar 17, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 153 of the FMO3 protein (p.Pro153Leu). This variant is present in population databases (rs72549326, gnomAD 0.2%). This missense change has been observed in individual(s) with trimethylaminuria (PMID: 8401051, 9398858, 11191884, 12893987, 16601883, 17224546, 21422137, 31240165). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16308). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects FMO3 function (PMID: 9282831, 9398858, 9536088, 17531949). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 20, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM3, PS3, PS4_moderate -

FMO3-related disorder

Pathogenic:1

Jul 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FMO3 c.458C>T variant is predicted to result in the amino acid substitution p.Pro153Leu. This variant is recognized as one of the most common pathogenic variants associated with trimethylaminuria (Dolphin et al. 1997. PubMed ID: 9398858; Chalmers et al. 2006. PubMed ID: 16601883; Doyle. 2019. PubMed ID: 31240165). We interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T

Eigen

Pathogenic

0.84

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.15

T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

4.6

H;.

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.9

D;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.99

D;.

Vest4

0.92

MVP

0.79

MPC

0.30

ClinPred

0.21

GERP RS

4.8

Varity_R

0.73

gMVP

0.74

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