chr1-171114034-C-T

Position:

chr1-171114034-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001002294.3(FMO3):c.855C>T(p.Asn285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,607,532 control chromosomes in the GnomAD database, including 59,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7980 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51513 hom. )

Consequence

FMO3
NM_001002294.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.534

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 1-171114034-C-T is Benign according to our data. Variant chr1-171114034-C-T is described in ClinVar as [Benign]. Clinvar id is 260078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-171114034-C-T is described in Lovd as [Benign]. Variant chr1-171114034-C-T is described in Lovd as [Likely_pathogenic].

BP7

Synonymous conserved (PhyloP=-0.534 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 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.855C>T	p.Asn285=	synonymous_variant	7/9	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.855C>T	p.Asn285=	synonymous_variant	7/9	1	NM_001002294.3	ENSP00000356729	P1
	ENST00000669750.1 linkuse as main transcript	n.533+54070G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

47500

AN:

151874

Hom.:

7962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.438

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.374

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.278

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.267

GnomAD3 exomes

AF:

0.286

AC:

71338

AN:

249238

Hom.:

10948

AF XY:

0.274

AC XY:

36872

AN XY:

134748

show subpopulations

Gnomad AFR exome

AF:

0.440

Gnomad AMR exome

AF:

0.388

Gnomad ASJ exome

AF:

0.187

Gnomad EAS exome

AF:

0.366

Gnomad SAS exome

AF:

0.235

Gnomad FIN exome

AF:

0.282

Gnomad NFE exome

AF:

0.246

Gnomad OTH exome

AF:

0.246

GnomAD4 exome

AF:

0.260

AC:

379031

AN:

1455540

Hom.:

51513

Cov.:

AF XY:

0.258

AC XY:

186567

AN XY:

724140

show subpopulations

Gnomad4 AFR exome

AF:

0.445

Gnomad4 AMR exome

AF:

0.381

Gnomad4 ASJ exome

AF:

0.190

Gnomad4 EAS exome

AF:

0.374

Gnomad4 SAS exome

AF:

0.232

Gnomad4 FIN exome

AF:

0.287

Gnomad4 NFE exome

AF:

0.249

Gnomad4 OTH exome

AF:

0.258

GnomAD4 genome

AF:

0.313

AC:

47568

AN:

151992

Hom.:

7980

Cov.:

AF XY:

0.314

AC XY:

23316

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.439

Gnomad4 AMR

AF:

0.326

Gnomad4 ASJ

AF:

0.192

Gnomad4 EAS

AF:

0.375

Gnomad4 SAS

AF:

0.242

Gnomad4 FIN

AF:

0.278

Gnomad4 NFE

AF:

0.248

Gnomad4 OTH

AF:

0.268

Alfa

AF:

0.249

Hom.:

12065

Bravo

AF:

0.322

Asia WGS

AF:

0.329

AC:

1143

AN:

3478

EpiCase

AF:

0.224

EpiControl

AF:

0.224

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	- -

Trimethylaminuria

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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

-0.41

CADD

Benign

5.3

DANN

Benign

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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