Genetic Variant FMO2:p.Asp36Gly (chr1-171185820-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001460.5(FMO2):c.107A>G(p.Asp36Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0745 in 1,613,426 control chromosomes in the GnomAD database, including 5,132 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.073 ( 452 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4680 hom. )

Consequence

FMO2
NM_001460.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.29

Publications

36 publications found

Variant links:

Genes affected

FMO2 (HGNC:3770): (flavin containing dimethylaniline monoxygenase 2) This gene encodes a flavin-containing monooxygenase family member. It is an NADPH-dependent enzyme that catalyzes the N-oxidation of some primary alkylamines through an N-hydroxylamine intermediate. However, some human populations contain an allele (FMO2*2A) with a premature stop codon, resulting in a protein that is C-terminally-truncated, has no catalytic activity, and is likely degraded rapidly. This gene is found in a cluster with other related family members on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

FMO2 links:

ENSG00000231424 (HGNC:40240):

ENSG00000231424 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027392507).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO2	NM_001460.5 link	c.107A>G	p.Asp36Gly	missense_variant	Exon 2 of 9	ENST00000209929.10	NP_001451.2	Q99518Q5JPC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO2	ENST00000209929.10 link	c.107A>G	p.Asp36Gly	missense_variant	Exon 2 of 9	1	NM_001460.5	ENSP00000209929.8		Q99518

Frequencies

GnomAD3 genomes

AF:

0.0726

AC:

11042

AN:

152072

Hom.:

452

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0713

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0623

Gnomad ASJ

AF:

0.149

Gnomad EAS

AF:

0.134

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.0477

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0673

Gnomad OTH

AF:

0.0716

GnomAD2 exomes

AF:

0.0795

AC:

19983

AN:

251384

AF XY:

0.0832

show subpopulations

Gnomad AFR exome

AF:

0.0685

Gnomad AMR exome

AF:

0.0457

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.135

Gnomad FIN exome

AF:

0.0485

Gnomad NFE exome

AF:

0.0700

Gnomad OTH exome

AF:

0.0882

GnomAD4 exome

AF:

0.0747

AC:

109211

AN:

1461236

Hom.:

4680

Cov.:

AF XY:

0.0768

AC XY:

55794

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.0693

AC:

2318

AN:

33454

American (AMR)

AF:

0.0470

AC:

2100

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

3990

AN:

26118

East Asian (EAS)

AF:

0.123

AC:

4900

AN:

39690

South Asian (SAS)

AF:

0.123

AC:

10647

AN:

86226

European-Finnish (FIN)

AF:

0.0515

AC:

2749

AN:

53412

Middle Eastern (MID)

AF:

0.134

AC:

772

AN:

5750

European-Non Finnish (NFE)

AF:

0.0689

AC:

76572

AN:

1111508

Other (OTH)

AF:

0.0855

AC:

5163

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

4677

9353

14030

18706

23383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3006

6012

9018

12024

15030

<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:

0.0726

AC:

11044

AN:

152190

Hom.:

452

Cov.:

AF XY:

0.0729

AC XY:

5423

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0713

AC:

2960

AN:

41508

American (AMR)

AF:

0.0623

AC:

952

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

517

AN:

3466

East Asian (EAS)

AF:

0.133

AC:

691

AN:

5180

South Asian (SAS)

AF:

0.127

AC:

614

AN:

4822

European-Finnish (FIN)

AF:

0.0477

AC:

506

AN:

10598

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0673

AC:

4576

AN:

68010

Other (OTH)

AF:

0.0718

AC:

152

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

548

1096

1645

2193

2741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<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:

0.0740

Hom.:

2121

Bravo

AF:

0.0720

TwinsUK

AF:

0.0715

AC:

265

ALSPAC

AF:

0.0643

AC:

248

ESP6500AA

AF:

0.0658

AC:

290

ESP6500EA

AF:

0.0678

AC:

583

ExAC

AF:

0.0815

AC:

9890

Asia WGS

AF:

0.117

AC:

405

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.45

PhyloP100

9.3

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.8

D;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.017

D;T

Vest4

0.25

ClinPred

0.044

GERP RS

5.7

PromoterAI

-0.036

Neutral

(source)

gMVP

0.75

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Computational scores

Splicing

Publications

Other links and lift over