1-171199445-C-T

Variant names:

• chr1-171199445-C-T
• rs2020862
• NM_001460.5:c.584C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001460.5(FMO2):​c.584C>T​(p.Ser195Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,610,546 control chromosomes in the GnomAD database, including 104,710 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.

• Frequency:
  • Genomes: 𝑓 0.40 (12670 hom., cov: 31)
  • Exomes 𝑓: 0.35 (92040 hom.)
• Consequence: FMO2 NM_001460.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80
• Publications: 42 publications found

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]

ENSG00000225243 (HGNC:):

ENSG00000231424 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011894703).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO2	NM_001460.5	MANE Select	c.584C>T	p.Ser195Leu	missense	Exon 5 of 9	NP_001451.2
	FMO2	NM_001365900.2		c.389C>T	p.Ser130Leu	missense	Exon 4 of 8	NP_001352829.1
	FMO2	NM_001301347.2		c.-34+2634C>T		intron	N/A	NP_001288276.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO2	ENST00000209929.10	TSL:1 MANE Select	c.584C>T	p.Ser195Leu	missense	Exon 5 of 9	ENSP00000209929.8
	ENSG00000225243	ENST00000422841.5	TSL:3	n.457G>A		non_coding_transcript_exon	Exon 3 of 3
	ENSG00000225243	ENST00000445290.1	TSL:2	n.209G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60048 AN: 151452 Hom.: 12643 Cov.: 31

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.383

GnomAD2 exomes AF: 0.398 AC: 99274 AN: 249350 AF XY: 0.392

Gnomad AFR exome AF: 0.514

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.496

Gnomad EAS exome AF: 0.558

Gnomad FIN exome AF: 0.280

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.347 AC: 506994 AN: 1458976 Hom.: 92040 Cov.: 34 AF XY: 0.350 AC XY: 253953 AN XY: 725790

African (AFR) AF: 0.515 AC: 17178 AN: 33354

American (AMR) AF: 0.509 AC: 22633 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 12973 AN: 26064

East Asian (EAS) AF: 0.530 AC: 20972 AN: 39556

South Asian (SAS) AF: 0.477 AC: 40931 AN: 85784

European-Finnish (FIN) AF: 0.278 AC: 14857 AN: 53360

Middle Eastern (MID) AF: 0.425 AC: 2446 AN: 5750

European-Non Finnish (NFE) AF: 0.317 AC: 352352 AN: 1110344

Other (OTH) AF: 0.376 AC: 22652 AN: 60294

GnomAD4 genome AF: 0.397 AC: 60123 AN: 151570 Hom.: 12670 Cov.: 31 AF XY: 0.398 AC XY: 29476 AN XY: 74062

African (AFR) AF: 0.508 AC: 20965 AN: 41282

American (AMR) AF: 0.457 AC: 6950 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1722 AN: 3466

East Asian (EAS) AF: 0.549 AC: 2797 AN: 5094

South Asian (SAS) AF: 0.494 AC: 2374 AN: 4808

European-Finnish (FIN) AF: 0.266 AC: 2805 AN: 10538

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.313 AC: 21261 AN: 67872

Other (OTH) AF: 0.386 AC: 812 AN: 2104

Alfa AF: 0.347 Hom.: 45718

Bravo AF: 0.419

TwinsUK AF: 0.323 AC: 1196

ALSPAC AF: 0.302 AC: 1164

ESP6500AA AF: 0.493 AC: 2174

ESP6500EA AF: 0.320 AC: 2753

ExAC AF: 0.396 AC: 48078

Asia WGS AF: 0.505 AC: 1758 AN: 3478

EpiCase AF: 0.332

EpiControl AF: 0.325

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0012	T
MetaSVM	Uncertain	-0.027	T
PhyloP100		7.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.35
ClinPred		0.12	T
GERP RS		6.2
gMVP		0.73
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2020862; hg19: chr1-171168584; COSMIC: COSV52947085; COSMIC: COSV52947085;