1-171205550-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001460.5(FMO2):c.1099G>A(p.Ala367Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,613,734 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A367V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (1 hom.)
• Consequence: FMO2 NM_001460.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO2	NM_001460.5	c.1099G>A	p.Ala367Thr	missense_variant	7/9	ENST00000209929.10
LOC124900413	XR_007066731.1	n.366-8612C>T		intron_variant, non_coding_transcript_variant
LOC105371611	XR_922278.4	n.515-37362C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO2	ENST00000209929.10	c.1099G>A	p.Ala367Thr	missense_variant	7/9	1	NM_001460.5	P1
	ENST00000445290.1	n.139-6035C>T		intron_variant, non_coding_transcript_variant		2
	ENST00000669750.1	n.449-37362C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000133 AC: 33 AN: 248830 Hom.: 1 AF XY: 0.000134 AC XY: 18 AN XY: 134668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461568 Hom.: 1 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 727074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.1099G>A (p.A367T) alteration is located in exon 7 (coding exon 6) of the FMO2 gene. This alteration results from a G to A substitution at nucleotide position 1099, causing the alanine (A) at amino acid position 367 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Vest4		0.43
MutPred		0.82		Loss of sheet (P = 0.1158);
MVP		0.65
ClinPred		0.58	D
GERP RS		5.0
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs529847680; hg19: chr1-171174689; COSMIC: COSV105071130; COSMIC: COSV105071130;