rs2266782

Positions:

chr1-171107825-G-A

Variant summary

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

The NM_001002294.3(FMO3):c.472G>A(p.Glu158Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,613,236 control chromosomes in the GnomAD database, including 133,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 12999 hom., cov: 32)

Exomes 𝑓: 0.40 ( 120066 hom. )

Consequence

FMO3
NM_001002294.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.221

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:

(HGNC:):

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=7.8064203E-4).

BP6

Variant 1-171107825-G-A is Benign according to our data. Variant chr1-171107825-G-A is described in ClinVar as [Benign]. Clinvar id is 38394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-171107825-G-A is described in Lovd as [Benign]. Variant chr1-171107825-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-171107825-G-A is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMO3	NM_001002294.3 linkuse as main transcript	c.472G>A	p.Glu158Lys	missense_variant	4/9	ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9 linkuse as main transcript	c.472G>A	p.Glu158Lys	missense_variant	4/9	1	NM_001002294.3	ENSP00000356729	P1
	ENST00000669750.1 linkuse as main transcript	n.533+60279C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.407

AC:

61759

AN:

151854

Hom.:

12984

Cov.:

show subpopulations

Gnomad AFR

AF:

0.459

Gnomad AMI

AF:

0.240

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.314

Gnomad EAS

AF:

0.202

Gnomad SAS

AF:

0.331

Gnomad FIN

AF:

0.440

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.417

Gnomad OTH

AF:

0.379

GnomAD3 exomes

AF:

0.374

AC:

93922

AN:

251054

Hom.:

18420

AF XY:

0.374

AC XY:

50729

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.466

Gnomad AMR exome

AF:

0.305

Gnomad ASJ exome

AF:

0.315

Gnomad EAS exome

AF:

0.201

Gnomad SAS exome

AF:

0.330

Gnomad FIN exome

AF:

0.441

Gnomad NFE exome

AF:

0.415

Gnomad OTH exome

AF:

0.360

GnomAD4 exome

AF:

0.401

AC:

586405

AN:

1461262

Hom.:

120066

Cov.:

AF XY:

0.400

AC XY:

290715

AN XY:

726942

show subpopulations

Gnomad4 AFR exome

AF:

0.463

Gnomad4 AMR exome

AF:

0.304

Gnomad4 ASJ exome

AF:

0.317

Gnomad4 EAS exome

AF:

0.202

Gnomad4 SAS exome

AF:

0.339

Gnomad4 FIN exome

AF:

0.447

Gnomad4 NFE exome

AF:

0.417

Gnomad4 OTH exome

AF:

0.382

GnomAD4 genome

AF:

0.407

AC:

61800

AN:

151974

Hom.:

12999

Cov.:

AF XY:

0.404

AC XY:

29988

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.459

Gnomad4 AMR

AF:

0.325

Gnomad4 ASJ

AF:

0.314

Gnomad4 EAS

AF:

0.202

Gnomad4 SAS

AF:

0.331

Gnomad4 FIN

AF:

0.440

Gnomad4 NFE

AF:

0.417

Gnomad4 OTH

AF:

0.376

Alfa

AF:

0.400

Hom.:

32259

Bravo

AF:

0.400

TwinsUK

AF:

0.408

AC:

1512

ALSPAC

AF:

0.417

AC:

1609

ESP6500AA

AF:

0.465

AC:

2050

ESP6500EA

AF:

0.410

AC:

3530

ExAC

AF:

0.383

AC:

46481

Asia WGS

AF:

0.243

AC:

847

AN:

3478

EpiCase

AF:

0.394

EpiControl

AF:

0.396

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32653296, 23510775, 31240165, 19321370, 17531949, 10479479, 11773868, 23211429, 10896299, 23791655, 23266626, 17142560, 12814961, 9282831, 17584019, 25870212, 11136294) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Trimethylaminuria

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

See cases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 28, 2022

ACMG classification criteria: BA1, BS1, BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.51

MetaRNN

Benign

0.00078

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.99

P;P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

REVEL

Benign

0.10

Sift

Benign

0.56

Sift4G

Benign

0.47

Polyphen

0.0060

Vest4

0.042

MPC

0.067

ClinPred

0.0062

GERP RS

3.8

Varity_R

0.13

gMVP

0.30

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

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