Genetic Variant FMO3:p.Asn61Ser (chr1-171103834-A-G) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM2PP3PP5_Very_Strong

The NM_001002294.3(FMO3):c.182A>G(p.Asn61Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004038298: Publications report experimental evidence evaluating an impact on protein function, finding a variant effect resulting in <10% of normal trimethylamine metabolism and NADPH binding affinity (Dolphin_2000, Yeung_2007, Gao_2017). PMID:29116146, 31580948, 11191884, 17531949." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

FMO3
NM_001002294.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 9.25

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:

FMO1-AS1 (HGNC:40240):

FMO1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004038298: Publications report experimental evidence evaluating an impact on protein function, finding a variant effect resulting in <10% of normal trimethylamine metabolism and NADPH binding affinity (Dolphin_2000, Yeung_2007, Gao_2017). PMID: 29116146, 31580948, 11191884, 17531949.; SCV006322986: Relevant functional assessments of this variant are available in the literature (PMID: 11191884, 17531949, 29116146).

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

PP5

Variant 1-171103834-A-G is Pathogenic according to our data. Variant chr1-171103834-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
FMO3	NM_001002294.3	MANE Select	c.182A>G	p.Asn61Ser	missense	Exon 3 of 9	NP_001002294.1	A0A024R8Z4
FMO3	NM_006894.6		c.182A>G	p.Asn61Ser	missense	Exon 3 of 9	NP_008825.4
FMO3	NM_001319173.2		c.122A>G	p.Asn41Ser	missense	Exon 4 of 10	NP_001306102.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FMO3	ENST00000367755.9	TSL:1 MANE Select	c.182A>G	p.Asn61Ser	missense	Exon 3 of 9	ENSP00000356729.4	P31513
FMO3	ENST00000479749.1	TSL:5	c.182A>G	p.Asn61Ser	missense	Exon 3 of 6	ENSP00000477451.1	V9GZ60
FMO3	ENST00000896149.1		c.182A>G	p.Asn61Ser	missense	Exon 3 of 9	ENSP00000566208.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251252

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111854

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000132

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74228

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000108

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Trimethylaminuria (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.050

MutationAssessor

Pathogenic

4.6

PhyloP100

9.3

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.89

MVP

0.82

MPC

0.24

ClinPred

0.99

GERP RS

3.5

Varity_R

0.91

gMVP

0.84

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.39

Position offset: 1

DS_AL_spliceai

0.22

Position offset: -49

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