1-171107794-C-T

Position:

chr1-171107794-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001002294.3(FMO3):c.441C>T(p.Ser147Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,613,590 control chromosomes in the GnomAD database, including 7,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 798 hom., cov: 32)

Exomes 𝑓: 0.074 ( 6213 hom. )

Consequence

FMO3
NM_001002294.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.42

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:):

ENSG00000231424 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 1-171107794-C-T is Benign according to our data. Variant chr1-171107794-C-T is described in ClinVar as [Benign]. Clinvar id is 260073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-171107794-C-T is described in Lovd as [Benign]. Variant chr1-171107794-C-T is described in Lovd as [Likely_pathogenic].

BP7

Synonymous conserved (PhyloP=-1.42 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 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.441C>T	p.Ser147Ser	synonymous_variant	4/9	ENST00000367755.9	NP_001002294.1	P31513A0A024R8Z4Q53FW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9 linkuse as main transcript	c.441C>T	p.Ser147Ser	synonymous_variant	4/9	1	NM_001002294.3	ENSP00000356729.4		P31513
FMO3	ENST00000479749.1 linkuse as main transcript	c.441C>T	p.Ser147Ser	synonymous_variant	4/6	5		ENSP00000477451.1		V9GZ60

Frequencies

GnomAD3 genomes

AF:

0.0843

AC:

12815

AN:

151994

Hom.:

790

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0798

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.190

Gnomad ASJ

AF:

0.0813

Gnomad EAS

AF:

0.205

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.0414

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0533

Gnomad OTH

AF:

0.0809

GnomAD3 exomes

AF:

0.115

AC:

28765

AN:

251004

Hom.:

2655

AF XY:

0.110

AC XY:

14894

AN XY:

135636

show subpopulations

Gnomad AFR exome

AF:

0.0795

Gnomad AMR exome

AF:

0.281

Gnomad ASJ exome

AF:

0.0803

Gnomad EAS exome

AF:

0.200

Gnomad SAS exome

AF:

0.181

Gnomad FIN exome

AF:

0.0466

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0947

GnomAD4 exome

AF:

0.0743

AC:

108657

AN:

1461478

Hom.:

6213

Cov.:

AF XY:

0.0762

AC XY:

55397

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.0808

Gnomad4 AMR exome

AF:

0.274

Gnomad4 ASJ exome

AF:

0.0797

Gnomad4 EAS exome

AF:

0.200

Gnomad4 SAS exome

AF:

0.175

Gnomad4 FIN exome

AF:

0.0451

Gnomad4 NFE exome

AF:

0.0544

Gnomad4 OTH exome

AF:

0.0840

GnomAD4 genome

AF:

0.0844

AC:

12837

AN:

152112

Hom.:

798

Cov.:

AF XY:

0.0886

AC XY:

6589

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0798

Gnomad4 AMR

AF:

0.191

Gnomad4 ASJ

AF:

0.0813

Gnomad4 EAS

AF:

0.206

Gnomad4 SAS

AF:

0.186

Gnomad4 FIN

AF:

0.0414

Gnomad4 NFE

AF:

0.0533

Gnomad4 OTH

AF:

0.0839

Alfa

AF:

0.0664

Hom.:

1121

Bravo

AF:

0.0945

Asia WGS

AF:

0.197

AC:

682

AN:

3476

EpiCase

AF:

0.0590

EpiControl

AF:

0.0564

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Trimethylaminuria

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.9

DANN

Benign

0.56

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