rs2266782

chr1-171107825-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001002294.3(FMO3):c.472G>A(p.Glu158Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,613,236 control chromosomes in the GnomAD database, including 133,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12999 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120066 hom.)
• Consequence: FMO3 NM_001002294.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.221

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.8064203E-4).
• BP6: Variant 1-171107825-G-A is Benign according to our data. Variant chr1-171107825-G-A is described in ClinVar as [Benign]. Clinvar id is 38394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-171107825-G-A is described in Lovd as [Benign]. Variant chr1-171107825-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-171107825-G-A is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO3	NM_001002294.3	c.472G>A	p.Glu158Lys	missense_variant	4/9	ENST00000367755.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO3	ENST00000367755.9	c.472G>A	p.Glu158Lys	missense_variant	4/9	1	NM_001002294.3	P1
	ENST00000669750.1	n.533+60279C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61759 AN: 151854 Hom.: 12984 Cov.: 32

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.379

GnomAD3 exomes AF: 0.374 AC: 93922 AN: 251054 Hom.: 18420 AF XY: 0.374 AC XY: 50729 AN XY: 135670

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.330

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.401 AC: 586405 AN: 1461262 Hom.: 120066 Cov.: 43 AF XY: 0.400 AC XY: 290715 AN XY: 726942

Gnomad4 AFR exome AF: 0.463

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.317

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.447

Gnomad4 NFE exome AF: 0.417

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.407 AC: 61800 AN: 151974 Hom.: 12999 Cov.: 32 AF XY: 0.404 AC XY: 29988 AN XY: 74302

Gnomad4 AFR AF: 0.459

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.440

Gnomad4 NFE AF: 0.417

Gnomad4 OTH AF: 0.376

Alfa AF: 0.400 Hom.: 32259

Bravo AF: 0.400

TwinsUK AF: 0.408 AC: 1512

ALSPAC AF: 0.417 AC: 1609

ESP6500AA AF: 0.465 AC: 2050

ESP6500EA AF: 0.410 AC: 3530

ExAC AF: 0.383 AC: 46481

Asia WGS AF: 0.243 AC: 847 AN: 3478

EpiCase AF: 0.394

EpiControl AF: 0.396

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32653296, 23510775, 31240165, 19321370, 17531949, 10479479, 11773868, 23211429, 10896299, 23791655, 23266626, 17142560, 12814961, 9282831, 17584019, 25870212, 11136294) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Trimethylaminuria Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

See cases Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 28, 2022

ACMG classification criteria: BA1, BS1, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.00078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.99	P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.56	T
Sift4G	Benign	0.47	T
Polyphen		0.0060	B
Vest4		0.042
MPC		0.067
ClinPred		0.0062	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2266782; hg19: chr1-171076966; COSMIC: COSV63006313; COSMIC: COSV63006313;