rs1920149

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.485-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 1,610,230 control chromosomes in the GnomAD database, including 193,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 22765 hom., cov: 32)

Exomes 𝑓: 0.48 ( 170798 hom. )

Consequence

FMO3
NM_001002294.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.424

Publications

17 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:

ENSG00000231424 (HGNC:40240):

ENSG00000231424 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=-0.89).

BP6

Variant 1-171108057-G-A is Benign according to our data. Variant chr1-171108057-G-A is described in ClinVar as Benign. ClinVar VariationId is 260074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3 link	c.485-22G>A		intron_variant	Intron 4 of 8	ENST00000367755.9	NP_001002294.1	P31513A0A024R8Z4Q53FW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9 link	c.485-22G>A		intron_variant	Intron 4 of 8	1	NM_001002294.3	ENSP00000356729.4		P31513
FMO3	ENST00000479749.1 link	c.468-59G>A		intron_variant	Intron 4 of 5	5		ENSP00000477451.1		V9GZ60

Frequencies

GnomAD3 genomes

AF:

0.537

AC:

81527

AN:

151808

Hom.:

22721

Cov.:

show subpopulations

Gnomad AFR

AF:

0.700

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.530

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.407

Gnomad SAS

AF:

0.516

Gnomad FIN

AF:

0.481

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.471

Gnomad OTH

AF:

0.496

GnomAD2 exomes

AF:

0.500

AC:

125500

AN:

250838

AF XY:

0.492

show subpopulations

Gnomad AFR exome

AF:

0.704

Gnomad AMR exome

AF:

0.594

Gnomad ASJ exome

AF:

0.395

Gnomad EAS exome

AF:

0.401

Gnomad FIN exome

AF:

0.487

Gnomad NFE exome

AF:

0.470

Gnomad OTH exome

AF:

0.461

GnomAD4 exome

AF:

0.481

AC:

700864

AN:

1458304

Hom.:

170798

Cov.:

AF XY:

0.480

AC XY:

348607

AN XY:

725606

show subpopulations

African (AFR)

AF:

0.712

AC:

23767

AN:

33390

American (AMR)

AF:

0.586

AC:

26196

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.397

AC:

10360

AN:

26112

East Asian (EAS)

AF:

0.402

AC:

15955

AN:

39666

South Asian (SAS)

AF:

0.515

AC:

44419

AN:

86204

European-Finnish (FIN)

AF:

0.492

AC:

26254

AN:

53402

Middle Eastern (MID)

AF:

0.439

AC:

2523

AN:

5752

European-Non Finnish (NFE)

AF:

0.471

AC:

522552

AN:

1108836

Other (OTH)

AF:

0.478

AC:

28838

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

17743

35486

53228

70971

88714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15628

31256

46884

62512

78140

<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:

0.537

AC:

81631

AN:

151926

Hom.:

22765

Cov.:

AF XY:

0.537

AC XY:

39850

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.701

AC:

29029

AN:

41436

American (AMR)

AF:

0.530

AC:

8082

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

1372

AN:

3468

East Asian (EAS)

AF:

0.408

AC:

2109

AN:

5170

South Asian (SAS)

AF:

0.515

AC:

2483

AN:

4820

European-Finnish (FIN)

AF:

0.481

AC:

5068

AN:

10528

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.471

AC:

32006

AN:

67938

Other (OTH)

AF:

0.496

AC:

1047

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1861

3722

5582

7443

9304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

710

1420

2130

2840

3550

<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:

0.488

Hom.:

24929

Bravo

AF:

0.547

Asia WGS

AF:

0.457

AC:

1590

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Trimethylaminuria

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.045

(source)

DANN

Benign

0.24

PhyloP100

-0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over