rs1736557
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_001002294.3(FMO3):c.769G>A(p.Val257Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,613,770 control chromosomes in the GnomAD database, including 5,296 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_001002294.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FMO3 | NM_001002294.3 | c.769G>A | p.Val257Met | missense_variant | Exon 6 of 9 | ENST00000367755.9 | NP_001002294.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0654 AC: 9948AN: 152106Hom.: 405 Cov.: 32
GnomAD3 exomes AF: 0.0815 AC: 20473AN: 251052Hom.: 1103 AF XY: 0.0819 AC XY: 11107AN XY: 135644
GnomAD4 exome AF: 0.0758 AC: 110765AN: 1461546Hom.: 4889 Cov.: 32 AF XY: 0.0760 AC XY: 55230AN XY: 727094
GnomAD4 genome AF: 0.0654 AC: 9958AN: 152224Hom.: 407 Cov.: 32 AF XY: 0.0662 AC XY: 4930AN XY: 74416
ClinVar
Submissions by phenotype
Trimethylaminuria Pathogenic:1Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not specified Benign:2
Variant summary: FMO3 c.769G>A (p.Val257Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.082 in 251052 control chromosomes in the gnomAD database, including 1103 homozygotes. The observed variant frequency is approximately 14.59 fold of the estimated maximal expected allele frequency for a pathogenic variant in FMO3 causing Trimethylaminuria phenotype (0.0056), which is stand-alone evidence that the variant is benign. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed the variant had no effect on enzyme activity (Stormer_2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic (OMIM), and one laboratory classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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not provided Benign:2
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at