1-171092708-C-T

Variant names:

• chr1-171092708-C-T
• NM_001002294.3:c.50C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001002294.3(FMO3):​c.50C>T​(p.Ser17Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FMO3 NM_001002294.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.95

Genes affected

FMO3 (HGNC:3771): (flavin containing dimethylaniline monoxygenase 3) Flavin-containing monooxygenases (FMO) are an important class of drug-metabolizing enzymes that catalyze the NADPH-dependent oxygenation of various nitrogen-,sulfur-, and phosphorous-containing xenobiotics such as therapeutic drugs, dietary compounds, pesticides, and other foreign compounds. The human FMO gene family is composed of 5 genes and multiple pseudogenes. FMO members have distinct developmental- and tissue-specific expression patterns. The expression of this FMO3 gene, the major FMO expressed in adult liver, can vary up to 20-fold between individuals. This inter-individual variation in FMO3 expression levels is likely to have significant effects on the rate at which xenobiotics are metabolised and, therefore, is of considerable interest to the pharmaceutical industry. This transmembrane protein localizes to the endoplasmic reticulum of many tissues. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. Mutations in this gene cause the disorder trimethylaminuria (TMAu) which is characterized by the accumulation and excretion of unmetabolized trimethylamine and a distinctive body odor. In healthy individuals, trimethylamine is primarily converted to the non odorous trimethylamine N-oxide.[provided by RefSeq, Jan 2016]

ENSG00000231424 (HGNC:40240):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.50C>T	p.Ser17Phe	missense_variant	Exon 2 of 9	ENST00000367755.9	NP_001002294.1
FMO3	NM_006894.6	c.50C>T	p.Ser17Phe	missense_variant	Exon 2 of 9		NP_008825.4
FMO3	NM_001319174.2	c.50C>T	p.Ser17Phe	missense_variant	Exon 2 of 8		NP_001306103.1
FMO3	NM_001319173.2	c.-138C>T		5_prime_UTR_variant	Exon 2 of 10		NP_001306102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.50C>T	p.Ser17Phe	missense_variant	Exon 2 of 9	1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.50C>T	p.Ser17Phe	missense_variant	Exon 2 of 6	5		ENSP00000477451.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

FMO3-related disorder Uncertain:1

Dec 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FMO3 c.50C>T variant is predicted to result in the amino acid substitution p.Ser17Phe. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.63
MutPred		0.79		Loss of phosphorylation at S17 (P = 0.0541);Loss of phosphorylation at S17 (P = 0.0541);
MVP		0.70
MPC		0.28
ClinPred		0.95	D
GERP RS		3.5
Varity_R		0.79
gMVP		0.80

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-171061849;