Genetic Variant FMO2:p.Cys530PhefsTer24 (chr1-171209118-C-CTT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001460.5(FMO2):c.1587_1588dupTT(p.Cys530PhefsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 679,018 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

FMO2
NM_001460.5 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.47

Publications

4 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:

ENSG00000231424 (HGNC:40240):

ENSG00000231424 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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
FMO2	NM_001460.5	MANE Select	c.1587_1588dupTT	p.Cys530PhefsTer24	frameshift	Exon 9 of 9	NP_001451.2
FMO2	NM_001365900.2		c.1392_1393dupTT	p.Cys465PhefsTer24	frameshift	Exon 8 of 8	NP_001352829.1
FMO2	NM_001301347.2		c.927_928dupTT	p.Cys310PhefsTer24	frameshift	Exon 7 of 7	NP_001288276.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FMO2	ENST00000209929.10	TSL:1 MANE Select	c.1587_1588dupTT	p.Cys530PhefsTer24	frameshift	Exon 9 of 9	ENSP00000209929.8
FMO2	ENST00000488431.1	TSL:2	n.579_580dupTT		non_coding_transcript_exon	Exon 2 of 2
FMO2	ENST00000529935.5	TSL:2	n.910_911dupTT		non_coding_transcript_exon	Exon 7 of 7	ENSP00000487002.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151222

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:

0.000388

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

527680

Hom.:

Cov.:

AF XY:

0.0000109

AC XY:

AN XY:

275338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13598

American (AMR)

AF:

0.0000554

AC:

AN:

18058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13816

East Asian (EAS)

AF:

0.000130

AC:

AN:

30804

South Asian (SAS)

AF:

0.0000236

AC:

AN:

42336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2100

European-Non Finnish (NFE)

AF:

0.00000868

AC:

AN:

345524

Other (OTH)

AF:

0.00

AC:

AN:

28438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

151338

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41226

American (AMR)

AF:

0.00

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000389

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67836

Other (OTH)

AF:

0.00

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-171209118-CT-CTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over