1-171199432-G-A

Variant names:

• chr1-171199432-G-A
• NM_001460.5:c.571G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001460.5(FMO2):​c.571G>A​(p.Gly191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FMO2 NM_001460.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

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.571G>A	p.Gly191Arg	missense	Exon 5 of 9	NP_001451.2	Q99518
	FMO2	NM_001365900.2		c.376G>A	p.Gly126Arg	missense	Exon 4 of 8	NP_001352829.1
	FMO2	NM_001301347.2		c.-34+2621G>A		intron	N/A	NP_001288276.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO2	ENST00000209929.10	TSL:1 MANE Select	c.571G>A	p.Gly191Arg	missense	Exon 5 of 9	ENSP00000209929.8	Q99518
	FMO2	ENST00000895514.1		c.571G>A	p.Gly191Arg	missense	Exon 5 of 9	ENSP00000565573.1
	FMO2	ENST00000895513.1		c.568G>A	p.Gly190Arg	missense	Exon 5 of 9	ENSP00000565572.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460638 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726628

African (AFR) AF: 0.0000300 AC: 1 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111468

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		9.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.86
MutPred		0.98		Gain of MoRF binding (P = 0.057)
MVP		0.99
ClinPred		1.0	D
GERP RS		6.2
gMVP		0.77
Mutation Taster		=70/30	polymorphism

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

hg19: chr1-171168571; COSMIC: COSV104569959; COSMIC: COSV104569959;