Genetic Variant FMO3:p.Asn285Asn (chr1-171114034-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006894.6(FMO3):c.855C>T(p.Asn285Asn) 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_006894.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.534

Publications

45 publications found

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 Gene-Disease associations (from GenCC):

trimethylaminuria
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
severe primary trimethylaminuria
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

FMO3 links:

FMO1-AS1 (HGNC:40240):

FMO1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 260078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006894.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FMO3	NM_001002294.3	MANE Select	c.855C>T	p.Asn285Asn	synonymous	Exon 7 of 9	NP_001002294.1
FMO3	NM_006894.6		c.855C>T	p.Asn285Asn	synonymous	Exon 7 of 9	NP_008825.4
FMO3	NM_001319173.2		c.795C>T	p.Asn265Asn	synonymous	Exon 8 of 10	NP_001306102.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FMO3	ENST00000367755.9	TSL:1 MANE Select	c.855C>T	p.Asn285Asn	synonymous	Exon 7 of 9	ENSP00000356729.4
FMO3	ENST00000896149.1		c.855C>T	p.Asn285Asn	synonymous	Exon 7 of 9	ENSP00000566208.1
FMO3	ENST00000896150.1		c.855C>T	p.Asn285Asn	synonymous	Exon 8 of 10	ENSP00000566209.1

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

GnomAD2 exomes

AF:

0.286

AC:

71338

AN:

249238

AF XY:

0.274

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 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

African (AFR)

AF:

0.445

AC:

14796

AN:

33228

American (AMR)

AF:

0.381

AC:

16905

AN:

44322

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

4947

AN:

25976

East Asian (EAS)

AF:

0.374

AC:

14828

AN:

39636

South Asian (SAS)

AF:

0.232

AC:

19952

AN:

85834

European-Finnish (FIN)

AF:

0.287

AC:

15304

AN:

53312

Middle Eastern (MID)

AF:

0.148

AC:

851

AN:

5746

European-Non Finnish (NFE)

AF:

0.249

AC:

275911

AN:

1107358

Other (OTH)

AF:

0.258

AC:

15537

AN:

60128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

12156

24313

36469

48626

60782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9608

19216

28824

38432

48040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.313

AC:

47568

AN:

151992

Hom.:

7980

Cov.:

AF XY:

0.314

AC XY:

23316

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.439

AC:

18173

AN:

41442

American (AMR)

AF:

0.326

AC:

4984

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

667

AN:

3468

East Asian (EAS)

AF:

0.375

AC:

1939

AN:

5168

South Asian (SAS)

AF:

0.242

AC:

1167

AN:

4818

European-Finnish (FIN)

AF:

0.278

AC:

2929

AN:

10550

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.248

AC:

16871

AN:

67968

Other (OTH)

AF:

0.268

AC:

564

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1603

3207

4810

6414

8017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.264

Hom.:

20848

Bravo

AF:

0.322

Asia WGS

AF:

0.329

AC:

1143

AN:

3478

EpiCase

AF:

0.224

EpiControl

AF:

0.224

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Trimethylaminuria (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

5.3

(source)

DANN

Benign

0.40

PhyloP100

-0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over