rs72549326

Positions:

• chr1-171107811-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3 PP5 BP4 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1 O:1
• 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]

(HGNC:):

ACMG classification

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: 215 AN: 152104 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00102 AC: 256 AN: 251080 Hom.: 0 AF XY: 0.00101 AC XY: 137 AN XY: 135676

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00247 AC: 3608 AN: 1461688 Hom.: 3 Cov.: 32 AF XY: 0.00230 AC XY: 1669 AN XY: 727146

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152104 Hom.: 1 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74302

Gnomad4 AFR AF: 0.000604

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00219 Hom.: 0

Bravo AF: 0.00168

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.000988 AC: 120

EpiCase AF: 0.00262

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Trimethylaminuria Pathogenic:4 Other: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:2 Uncertain: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.6	H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.9	D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;.
Vest4		0.92
MVP		0.79
MPC		0.30
ClinPred		0.21	T
GERP RS		4.8
Varity_R		0.73
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs72549326; hg19: chr1-171076952;