rs909531

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001002294.3(FMO3):c.1183+35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,419,972 control chromosomes in the GnomAD database, including 30,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4675 hom., cov: 32)

Exomes 𝑓: 0.19 ( 25353 hom. )

Consequence

FMO3
NM_001002294.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0140

Publications

11 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-171114397-T-C is Benign according to our data. Variant chr1-171114397-T-C is described in ClinVar as Benign. ClinVar VariationId is 260064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002294.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FMO3	NM_001002294.3	MANE Select	c.1183+35T>C	intron	N/A	NP_001002294.1	A0A024R8Z4
FMO3	NM_006894.6		c.1183+35T>C	intron	N/A	NP_008825.4
FMO3	NM_001319173.2		c.1123+35T>C	intron	N/A	NP_001306102.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FMO3	ENST00000367755.9	TSL:1 MANE Select	c.1183+35T>C	intron	N/A	ENSP00000356729.4	P31513
FMO3	ENST00000896149.1		c.1183+35T>C	intron	N/A	ENSP00000566208.1
FMO3	ENST00000896150.1		c.1183+35T>C	intron	N/A	ENSP00000566209.1

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35134

AN:

151958

Hom.:

4663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.362

Gnomad AMI

AF:

0.137

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.0520

Gnomad FIN

AF:

0.237

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.198

Gnomad OTH

AF:

0.193

GnomAD2 exomes

AF:

0.178

AC:

38530

AN:

216176

AF XY:

0.171

show subpopulations

Gnomad AFR exome

AF:

0.374

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.187

Gnomad FIN exome

AF:

0.243

Gnomad NFE exome

AF:

0.204

Gnomad OTH exome

AF:

0.156

GnomAD4 exome

AF:

0.194

AC:

246086

AN:

1267896

Hom.:

25353

Cov.:

AF XY:

0.189

AC XY:

120455

AN XY:

638610

show subpopulations

African (AFR)

AF:

0.373

AC:

11169

AN:

29964

American (AMR)

AF:

0.109

AC:

4557

AN:

41968

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

2964

AN:

24674

East Asian (EAS)

AF:

0.187

AC:

7156

AN:

38166

South Asian (SAS)

AF:

0.0542

AC:

4368

AN:

80632

European-Finnish (FIN)

AF:

0.245

AC:

12729

AN:

51946

Middle Eastern (MID)

AF:

0.0620

AC:

331

AN:

5342

European-Non Finnish (NFE)

AF:

0.205

AC:

193075

AN:

941356

Other (OTH)

AF:

0.181

AC:

9737

AN:

53848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

9660

19321

28981

38642

48302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6398

12796

19194

25592

31990

<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:

0.231

AC:

35183

AN:

152076

Hom.:

4675

Cov.:

AF XY:

0.228

AC XY:

16956

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.362

AC:

14997

AN:

41468

American (AMR)

AF:

0.136

AC:

2083

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

407

AN:

3472

East Asian (EAS)

AF:

0.182

AC:

942

AN:

5164

South Asian (SAS)

AF:

0.0516

AC:

249

AN:

4824

European-Finnish (FIN)

AF:

0.237

AC:

2509

AN:

10580

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.198

AC:

13452

AN:

67978

Other (OTH)

AF:

0.192

AC:

404

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1322

2644

3966

5288

6610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.202

Hom.:

1782

Bravo

AF:

0.230

Asia WGS

AF:

0.131

AC:

454

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.0

(source)

DANN

Benign

0.65

PhyloP100

-0.014

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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