1-171199358-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.01

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• 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 id is 774280.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO2	NM_001460.5	c.497T>C	p.Phe166Ser	missense_variant	5/9	ENST00000209929.10
LOC124900413	XR_007066731.1	n.366-2420A>G		intron_variant, non_coding_transcript_variant
LOC105371611	XR_922278.4	n.515-31170A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO2	ENST00000209929.10	c.497T>C	p.Phe166Ser	missense_variant	5/9	1	NM_001460.5	P1
	ENST00000445290.1	n.296A>G		non_coding_transcript_exon_variant	2/2	2
	ENST00000669750.1	n.449-31170A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152176 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.00396 AC: 972 AN: 245418 Hom.: 2 AF XY: 0.00384 AC XY: 509 AN XY: 132490

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 SAS exome AF: 0.00116

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.: 26 Cov.: 30 AF XY: 0.00544 AC XY: 3938 AN XY: 723930

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00544

Gnomad4 ASJ exome AF: 0.00159

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000908

Gnomad4 FIN exome AF: 0.000733

Gnomad4 NFE exome AF: 0.00661

Gnomad4 OTH exome AF: 0.00550

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74474

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00644

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00571 Hom.: 6

Bravo AF: 0.00478

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00361 AC: 438

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Vest4		0.70
MVP		0.95
ClinPred		0.13	T
GERP RS		6.2
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs140394156; hg19: chr1-171168497; COSMIC: COSV99070656; COSMIC: COSV99070656;