rs72549326
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3PP5BP4BS2
The NM_001002294.3(FMO3):c.458C>T(p.Pro153Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,792 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0025 ( 3 hom. )
Consequence
FMO3
NM_001002294.3 missense
NM_001002294.3 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 7.85
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
?
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
PP5
?
Variant 1-171107811-C-T is Pathogenic according to our data. Variant chr1-171107811-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16308.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=5, Uncertain_significance=1}. Variant chr1-171107811-C-T is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15120038). . Strength limited to SUPPORTING due to the PP5.
BS2
?
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FMO3 | NM_001002294.3 | c.458C>T | p.Pro153Leu | missense_variant | 4/9 | ENST00000367755.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FMO3 | ENST00000367755.9 | c.458C>T | p.Pro153Leu | missense_variant | 4/9 | 1 | NM_001002294.3 | P1 | |
ENST00000669750.1 | n.533+60293G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00141 AC: 215AN: 152104Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00102 AC: 256AN: 251080Hom.: 0 AF XY: 0.00101 AC XY: 137AN XY: 135676
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GnomAD4 exome AF: 0.00247 AC: 3608AN: 1461688Hom.: 3 Cov.: 32 AF XY: 0.00230 AC XY: 1669AN XY: 727146
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GnomAD4 genome ? AF: 0.00141 AC: 215AN: 152104Hom.: 1 Cov.: 33 AF XY: 0.00122 AC XY: 91AN XY: 74302
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Trimethylaminuria Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 08, 2023 | Variant summary: FMO3 c.458C>T (p.Pro153Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 251080 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FMO3 causing Trimethylaminuria (0.001 vs 0.0056), allowing no conclusion about variant significance. c.458C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Trimethylaminuria (e.g., Dolphin_1997, Treacy_1998), and the variant has been shown to segregate with disease in related individuals (e.g., Dolphin_1997). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in undetectable or severely reduced (<10%) enzymatic activity relative to the wild type (e.g., Dolphin_1997, Treacy_1998, Yeung_2007). The following publications have been ascertained in the context of this evaluation (PMID: 9398858, 9536088, 17531949). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 3; VUS, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 02, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 06, 2017 | The FMO3 c.458C>T (p.Pro153Leu) missense variant is reported widely reported in the literature and is noted to be one of the most common variants in the FMO3 gene associated with disease (Philips et al. 2015). Across a selection of the available literature, the p.Pro153Leu variant was identified in a total of 14 individuals with trimethylaminuria, including eight homozygotes and six compound heterozygotes. Four unaffected family members were identified as heterozygotes for the p.Pro153Leu variant (Dolphin et al. 1997; Treacy et al. 1998; Dolphin et al. 2000; Chalmers et al. 2006). The variant was found in one of 108 control chromosomes, and is reported at a frequency of 0.00337 in the European American population of the Exome Sequencing Project. Functional analysis by several groups demonstrated that the p.Pro153Leu variant abolishes the catalytic activity of FMO3 (Dolphin et al. 1997; Cashman et al. 1997; Treacy et al. 1998). Based on the collective evidence, the p.Pro153Leu variant is classified as pathogenic for trimethylaminuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1997 | - - |
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 08, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 153 of the FMO3 protein (p.Pro153Leu). This variant is present in population databases (rs72549326, gnomAD 0.2%). This missense change has been observed in individual(s) with trimethylaminuria (PMID: 8401051, 9398858, 11191884, 12893987, 16601883, 17224546, 21422137, 31240165). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16308). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects FMO3 function (PMID: 9282831, 9398858, 9536088, 17531949). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 20, 2023 | PP3, PP4, PM3, PS3, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 17, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
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