1-171196784-C-A

Variant names:

• chr1-171196784-C-A
• rs1305667003
• NM_001460.5:c.457C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001460.5(FMO2):​c.457C>A​(p.Pro153Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P153S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FMO2 NM_001460.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• 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]

LOC124900413 (HGNC:):

FMO1-AS1 (HGNC:40240):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

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.457C>A	p.Pro153Thr	missense	Exon 4 of 9	NP_001451.2	Q99518
	FMO2	NM_001365900.2		c.262C>A	p.Pro88Thr	missense	Exon 3 of 8	NP_001352829.1
	FMO2	NM_001301347.2		c.-61C>A		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.457C>A	p.Pro153Thr	missense	Exon 4 of 9	ENSP00000209929.8	Q99518
	FMO2	ENST00000895514.1		c.457C>A	p.Pro153Thr	missense	Exon 4 of 9	ENSP00000565573.1
	FMO2	ENST00000895513.1		c.454C>A	p.Pro152Thr	missense	Exon 4 of 9	ENSP00000565572.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461234 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726908

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.064	T
PhyloP100		1.1
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Vest4		0.65
MutPred		0.77		Gain of glycosylation at P153 (P = 0.0357)
MVP		0.83
ClinPred		0.99	D
GERP RS		3.9
gMVP		0.56
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1305667003; hg19: chr1-171165923;