chr1-171282208-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001282693.2(FMO1):āc.1058A>Gā(p.Tyr353Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,614,012 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.00051 ( 1 hom., cov: 32)
Exomes š: 0.000049 ( 0 hom. )
Consequence
FMO1
NM_001282693.2 missense
NM_001282693.2 missense
Scores
8
6
3
Clinical Significance
Conservation
PhyloP100: 7.44
Genes affected
FMO1 (HGNC:3769): (flavin containing dimethylaniline monoxygenase 1) Metabolic N-oxidation of the diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man resulting in a small subpopulation with reduced TMA N-oxidation capacity resulting in fish odor syndrome Trimethylaminuria. Three forms of the enzyme, FMO1 found in fetal liver, FMO2 found in adult liver, and FMO3 are encoded by genes clustered in the 1q23-q25 region. Flavin-containing monooxygenases are NADPH-dependent flavoenzymes that catalyzes the oxidation of soft nucleophilic heteroatom centers in drugs, pesticides, and xenobiotics. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]
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ACMG classification
Classification made for transcript
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 |
---|---|---|---|---|---|---|---|
FMO1 | NM_001282693.2 | c.1058A>G | p.Tyr353Cys | missense_variant | 7/9 | ENST00000617670.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FMO1 | ENST00000617670.6 | c.1058A>G | p.Tyr353Cys | missense_variant | 7/9 | 1 | NM_001282693.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000486 AC: 74AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 250916Hom.: 0 AF XY: 0.0000811 AC XY: 11AN XY: 135680
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GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461682Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 727144
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GnomAD4 genome AF: 0.000512 AC: 78AN: 152330Hom.: 1 Cov.: 32 AF XY: 0.000564 AC XY: 42AN XY: 74494
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2024 | The c.1058A>G (p.Y353C) alteration is located in exon 7 (coding exon 6) of the FMO1 gene. This alteration results from a A to G substitution at nucleotide position 1058, causing the tyrosine (Y) at amino acid position 353 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;D;D;D
Vest4
MVP
MPC
0.62
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at