Genetic Variant NM_002022.3:c.662T>A (chr1-171332743-T-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002022.3(FMO4):c.662T>A(p.Leu221His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,611,478 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 22 hom. )

Consequence

FMO4
NM_002022.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.155

Publications

13 publications found

Variant links:

Genes affected

FMO4 (HGNC:3772): (flavin containing dimethylaniline monoxygenase 4) Metabolic N-oxidation of diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man. This results in a small subpopulation with reduced TMA N-oxidation capacity and causes fish odor syndrome (Trimethylaminuria). Three forms of the enzyme are encoded by genes clustered in the 1q23-q25 region. Flavin-containing monooxygenases are NADPH-dependent flavoenzymes that catalyzes the oxidation of soft nucleophilic heteroatom centers in drugs, pesticides, and xenobiotics. [provided by RefSeq, Jan 2015]

FMO4 links:

ENSG00000302209 (HGNC:):

ENSG00000302209 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011537373).

BP6

Variant 1-171332743-T-A is Benign according to our data. Variant chr1-171332743-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 718489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002022.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO4	NM_002022.3	MANE Select	c.662T>A	p.Leu221His	missense	Exon 7 of 10	NP_002013.1	P31512

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FMO4	ENST00000367749.4	TSL:1 MANE Select	c.662T>A	p.Leu221His	missense	Exon 7 of 10	ENSP00000356723.3	P31512
FMO4	ENST00000853715.1		c.662T>A	p.Leu221His	missense	Exon 7 of 10	ENSP00000523774.1
FMO4	ENST00000853716.1		c.662T>A	p.Leu221His	missense	Exon 8 of 11	ENSP00000523775.1

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

504

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00516

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00307

AC:

771

AN:

251114

AF XY:

0.00298

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00439

Gnomad NFE exome

AF:

0.00464

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00461

AC:

6725

AN:

1459158

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

3136

AN XY:

726118

show subpopulations

African (AFR)

AF:

0.000659

AC:

AN:

33402

American (AMR)

AF:

0.00181

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00513

AC:

134

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.000545

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00401

AC:

214

AN:

53406

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00534

AC:

5926

AN:

1109658

Other (OTH)

AF:

0.00493

AC:

297

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

316

632

949

1265

1581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

226

452

678

904

1130

<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:

0.00331

AC:

504

AN:

152320

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41570

American (AMR)

AF:

0.00275

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00555

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00516

AC:

351

AN:

68022

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

109

136

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:

0.00418

Hom.:

Bravo

AF:

0.00297

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00294

AC:

357

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00504

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

Benign

0.18

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.084

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.37

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.9

PhyloP100

0.15

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.19

Sift

Benign

0.043

Sift4G

Benign

0.082

Polyphen

0.97

Vest4

0.29

MVP

0.50

MPC

0.30

ClinPred

0.082

GERP RS

-5.2

Varity_R

0.29

gMVP

0.62

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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