Genetic Variant NM_001460.5:c.497T>C (chr1-171199358-T-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_001460.5(FMO2):c.497T>C(p.Phe166Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00544 in 1,608,106 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 26 hom. )

Consequence

FMO2
NM_001460.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.01

Publications

8 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:

ENSG00000225243 (HGNC:):

ENSG00000225243 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 -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.025721163).

BP6

Variant 1-171199358-T-C is Benign according to our data. Variant chr1-171199358-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 774280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001460.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FMO2	NM_001460.5	MANE Select	c.497T>C	p.Phe166Ser	missense	Exon 5 of 9	NP_001451.2	Q99518
FMO2	NM_001365900.2		c.302T>C	p.Phe101Ser	missense	Exon 4 of 8	NP_001352829.1
FMO2	NM_001301347.2		c.-34+2547T>C		intron	N/A	NP_001288276.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FMO2	ENST00000209929.10	TSL:1 MANE Select	c.497T>C	p.Phe166Ser	missense	Exon 5 of 9	ENSP00000209929.8	Q99518
FMO2	ENST00000895514.1		c.497T>C	p.Phe166Ser	missense	Exon 5 of 9	ENSP00000565573.1
FMO2	ENST00000895513.1		c.494T>C	p.Phe165Ser	missense	Exon 5 of 9	ENSP00000565572.1

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

624

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00688

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00644

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00396

AC:

972

AN:

245418

AF XY:

0.00384

show subpopulations

Gnomad AFR exome

AF:

0.00131

Gnomad AMR exome

AF:

0.00599

Gnomad ASJ exome

AF:

0.00185

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000234

Gnomad NFE exome

AF:

0.00597

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00558

AC:

8122

AN:

1455812

Hom.:

Cov.:

AF XY:

0.00544

AC XY:

3938

AN XY:

723930

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33228

American (AMR)

AF:

0.00544

AC:

240

AN:

44096

Ashkenazi Jewish (ASJ)

AF:

0.00159

AC:

AN:

25764

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.000908

AC:

AN:

84832

European-Finnish (FIN)

AF:

0.000733

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.00349

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00661

AC:

7334

AN:

1109302

Other (OTH)

AF:

0.00550

AC:

331

AN:

60162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

351

701

1052

1402

1753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.00410

AC:

624

AN:

152294

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

283

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41556

American (AMR)

AF:

0.00687

AC:

105

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000830

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00644

AC:

438

AN:

68030

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00548

Hom.:

Bravo

AF:

0.00478

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00361

AC:

438

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.026

MetaSVM

Uncertain

0.41

PhyloP100

5.0

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Vest4

0.70

MVP

0.95

ClinPred

0.13

GERP RS

6.2

gMVP

0.74

Mutation Taster

=75/25

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over