rs2020870

Positions:

• chr1-171185820-A-G

Variant summary

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

The NM_001460.5(FMO2):​c.107A>G​(p.Asp36Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0745 in 1,613,426 control chromosomes in the GnomAD database, including 5,132 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 0.073 (452 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4680 hom.)
• Consequence: FMO2 NM_001460.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29

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=0.0027392507).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO2	NM_001460.5	c.107A>G	p.Asp36Gly	missense_variant	2/9	ENST00000209929.10
LOC105371611	XR_922278.4	n.515-17632T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO2	ENST00000209929.10	c.107A>G	p.Asp36Gly	missense_variant	2/9	1	NM_001460.5	P1
	ENST00000669750.1	n.449-17632T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11042 AN: 152072 Hom.: 452 Cov.: 32

Gnomad AFR AF: 0.0713

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0673

Gnomad OTH AF: 0.0716

GnomAD3 exomes AF: 0.0795 AC: 19983 AN: 251384 Hom.: 1012 AF XY: 0.0832 AC XY: 11298 AN XY: 135868

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.0457

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.135

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0485

Gnomad NFE exome AF: 0.0700

Gnomad OTH exome AF: 0.0882

GnomAD4 exome AF: 0.0747 AC: 109211 AN: 1461236 Hom.: 4680 Cov.: 31 AF XY: 0.0768 AC XY: 55794 AN XY: 726922

Gnomad4 AFR exome AF: 0.0693

Gnomad4 AMR exome AF: 0.0470

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.0515

Gnomad4 NFE exome AF: 0.0689

Gnomad4 OTH exome AF: 0.0855

GnomAD4 genome AF: 0.0726 AC: 11044 AN: 152190 Hom.: 452 Cov.: 32 AF XY: 0.0729 AC XY: 5423 AN XY: 74402

Gnomad4 AFR AF: 0.0713

Gnomad4 AMR AF: 0.0623

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.0477

Gnomad4 NFE AF: 0.0673

Gnomad4 OTH AF: 0.0718

Alfa AF: 0.0747 Hom.: 1108

Bravo AF: 0.0720

TwinsUK AF: 0.0715 AC: 265

ALSPAC AF: 0.0643 AC: 248

ESP6500AA AF: 0.0658 AC: 290

ESP6500EA AF: 0.0678 AC: 583

ExAC AF: 0.0815 AC: 9890

Asia WGS AF: 0.117 AC: 405 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	0.0000047	P;P
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.017	D;T
Vest4		0.25
ClinPred		0.044	T
GERP RS		5.7
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2020870; hg19: chr1-171154959; COSMIC: COSV52949867;