rs2307492

chr1-171199406-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001460.5(FMO2):c.545T>C(p.Phe182Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,611,428 control chromosomes in the GnomAD database, including 8,507 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1177 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7330 hom.)
• Consequence: FMO2 NM_001460.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017034411).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO2	NM_001460.5	c.545T>C	p.Phe182Ser	missense_variant	5/9	ENST00000209929.10
LOC124900413	XR_007066731.1	n.366-2468A>G		intron_variant, non_coding_transcript_variant
LOC105371611	XR_922278.4	n.515-31218A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO2	ENST00000209929.10	c.545T>C	p.Phe182Ser	missense_variant	5/9	1	NM_001460.5	P1
	ENST00000445290.1	n.248A>G		non_coding_transcript_exon_variant	2/2	2
	ENST00000669750.1	n.449-31218A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17797 AN: 151984 Hom.: 1176 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.0443

Gnomad SAS AF: 0.0916

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0965

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.104 AC: 25912 AN: 249292 Hom.: 1530 AF XY: 0.103 AC XY: 13815 AN XY: 134742

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.0458

Gnomad EAS exome AF: 0.0446

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.0955

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.0963 AC: 140493 AN: 1459328 Hom.: 7330 Cov.: 30 AF XY: 0.0965 AC XY: 70088 AN XY: 725982

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.0345

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0940

Gnomad4 OTH exome AF: 0.0968

GnomAD4 genome AF: 0.117 AC: 17803 AN: 152100 Hom.: 1177 Cov.: 32 AF XY: 0.117 AC XY: 8734 AN XY: 74358

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.0442

Gnomad4 SAS AF: 0.0913

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.0965

Gnomad4 OTH AF: 0.105

Alfa AF: 0.0995 Hom.: 2074

Bravo AF: 0.120

TwinsUK AF: 0.0955 AC: 354

ALSPAC AF: 0.0983 AC: 379

ESP6500AA AF: 0.176 AC: 777

ESP6500EA AF: 0.0971 AC: 835

ExAC AF: 0.106 AC: 12856

Asia WGS AF: 0.0650 AC: 228 AN: 3478

EpiCase AF: 0.0913

EpiControl AF: 0.0922

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0017	T
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.23
ClinPred		0.13	T
GERP RS		5.0
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs2307492; hg19: chr1-171168545; COSMIC: COSV52947767; COSMIC: COSV52947767;