rs28369860

Variant names:

• chr1-171196663-TG-T
• rs28369860
• NM_001460.5:c.337delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001460.5(FMO2):​c.337delG​(p.Val113fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 1,612,710 control chromosomes in the GnomAD database, including 4,390 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.10 (1493 hom., cov: 31)
  • Exomes 𝑓: 0.051 (2897 hom.)
• Consequence: FMO2 NM_001460.5 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.92
• Publications: 16 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]

LOC124900413 (HGNC:):

FMO1-AS1 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-171196663-TG-T is Benign according to our data. Variant chr1-171196663-TG-T is described in ClinVar as Benign. ClinVar VariationId is 402870.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.256 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.337delG	p.Val113fs	frameshift	Exon 4 of 9	NP_001451.2	Q99518
	FMO2	NM_001365900.2		c.142delG	p.Val48fs	frameshift	Exon 3 of 8	NP_001352829.1
	FMO2	NM_001301347.2		c.-181delG		5_prime_UTR	Exon 3 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.337delG	p.Val113fs	frameshift	Exon 4 of 9	ENSP00000209929.8	Q99518
	FMO2	ENST00000895514.1		c.337delG	p.Val113fs	frameshift	Exon 4 of 9	ENSP00000565573.1
	FMO2	ENST00000895513.1		c.334delG	p.Val112fs	frameshift	Exon 4 of 9	ENSP00000565572.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15819 AN: 152080 Hom.: 1490 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0940

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0883

GnomAD2 exomes AF: 0.0567 AC: 14216 AN: 250882 AF XY: 0.0537

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.0361

Gnomad ASJ exome AF: 0.0896

Gnomad EAS exome AF: 0.000545

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.0467

Gnomad OTH exome AF: 0.0518

GnomAD4 exome AF: 0.0506 AC: 73873 AN: 1460512 Hom.: 2897 Cov.: 30 AF XY: 0.0499 AC XY: 36268 AN XY: 726604

African (AFR) AF: 0.269 AC: 8979 AN: 33434

American (AMR) AF: 0.0389 AC: 1738 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0871 AC: 2275 AN: 26132

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39686

South Asian (SAS) AF: 0.0528 AC: 4549 AN: 86190

European-Finnish (FIN) AF: 0.0235 AC: 1253 AN: 53402

Middle Eastern (MID) AF: 0.0782 AC: 402 AN: 5140

European-Non Finnish (NFE) AF: 0.0460 AC: 51088 AN: 1111570

Other (OTH) AF: 0.0594 AC: 3581 AN: 60284

GnomAD4 genome AF: 0.104 AC: 15844 AN: 152198 Hom.: 1493 Cov.: 31 AF XY: 0.101 AC XY: 7488 AN XY: 74412

African (AFR) AF: 0.260 AC: 10794 AN: 41472

American (AMR) AF: 0.0567 AC: 868 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0940 AC: 326 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0528 AC: 255 AN: 4826

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10612

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0463 AC: 3148 AN: 68020

Other (OTH) AF: 0.0874 AC: 185 AN: 2116

Alfa AF: 0.0354 Hom.: 33

Bravo AF: 0.114

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=147/53	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs28369860; hg19: chr1-171165802; COSMIC: COSV52950502; COSMIC: COSV52950502;