NM_001460.5:c.1476A>G

Variant names:

• chr1-171209013-A-G
• rs2020869
• NM_001460.5:c.1476A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001460.5(FMO2):​c.1476A>G​(p.Lys492Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,507,422 control chromosomes in the GnomAD database, including 17,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2032 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15148 hom.)
• Consequence: FMO2 NM_001460.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.564
• Publications: 14 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:):

FMO1-AS1 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-171209013-A-G is Benign according to our data. Variant chr1-171209013-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 769543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.564 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.234 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO2	NM_001460.5	MANE Select	c.1476A>G	p.Lys492Lys	synonymous	Exon 9 of 9	NP_001451.2
	FMO2	NM_001365900.2		c.1281A>G	p.Lys427Lys	synonymous	Exon 8 of 8	NP_001352829.1
	FMO2	NM_001301347.2		c.816A>G	p.Lys272Lys	synonymous	Exon 7 of 7	NP_001288276.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO2	ENST00000209929.10	TSL:1 MANE Select	c.1476A>G	p.Lys492Lys	synonymous	Exon 9 of 9	ENSP00000209929.8
	FMO2	ENST00000895514.1		c.1476A>G	p.Lys492Lys	synonymous	Exon 9 of 9	ENSP00000565573.1
	FMO2	ENST00000895513.1		c.1473A>G	p.Lys491Lys	synonymous	Exon 9 of 9	ENSP00000565572.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23768 AN: 151998 Hom.: 2026 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.145 AC: 196024 AN: 1355306 Hom.: 15148 Cov.: 19 AF XY: 0.145 AC XY: 98086 AN XY: 675514

African (AFR) AF: 0.170 AC: 5214 AN: 30586

American (AMR) AF: 0.298 AC: 11864 AN: 39784

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2722 AN: 23912

East Asian (EAS) AF: 0.197 AC: 7623 AN: 38792

South Asian (SAS) AF: 0.183 AC: 14667 AN: 80190

European-Finnish (FIN) AF: 0.120 AC: 6258 AN: 52340

Middle Eastern (MID) AF: 0.143 AC: 773 AN: 5416

European-Non Finnish (NFE) AF: 0.135 AC: 138381 AN: 1027954

Other (OTH) AF: 0.151 AC: 8522 AN: 56332

GnomAD4 genome AF: 0.156 AC: 23785 AN: 152116 Hom.: 2032 Cov.: 32 AF XY: 0.159 AC XY: 11829 AN XY: 74348

African (AFR) AF: 0.170 AC: 7054 AN: 41498

American (AMR) AF: 0.240 AC: 3667 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 409 AN: 3470

East Asian (EAS) AF: 0.223 AC: 1153 AN: 5164

South Asian (SAS) AF: 0.165 AC: 797 AN: 4816

European-Finnish (FIN) AF: 0.120 AC: 1268 AN: 10592

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9035 AN: 67990

Other (OTH) AF: 0.162 AC: 343 AN: 2116

Alfa AF: 0.145 Hom.: 7547

Bravo AF: 0.167

Asia WGS AF: 0.173 AC: 601 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.4
DANN	Benign	0.63
PhyloP100		0.56
Mutation Taster		=100/0	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: rs2020869; hg19: chr1-171178152; COSMIC: COSV52947060;