rs2266780

chr1-171114102-A-G

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.923A>G(p.Glu308Gly) variant causes a missense change. The variant allele was found at a frequency of 0.176 in 1,613,186 control chromosomes in the GnomAD database, including 27,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1936 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25663 hom.)
• Consequence: FMO3 NM_001002294.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.31

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=0.0016511381).
• BP6: Variant 1-171114102-A-G is Benign according to our data. Variant chr1-171114102-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 38395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-171114102-A-G is described in Lovd as [Benign]. Variant chr1-171114102-A-G is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO3	NM_001002294.3	c.923A>G	p.Glu308Gly	missense_variant	7/9	ENST00000367755.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO3	ENST00000367755.9	c.923A>G	p.Glu308Gly	missense_variant	7/9	1	NM_001002294.3	P1
	ENST00000669750.1	n.533+54002T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21104 AN: 152064 Hom.: 1936 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.150 AC: 37773 AN: 251032 Hom.: 3457 AF XY: 0.149 AC XY: 20219 AN XY: 135662

Gnomad AFR exome AF: 0.0370

Gnomad AMR exome AF: 0.0888

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.0489

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.180 AC: 262373 AN: 1461004 Hom.: 25663 Cov.: 33 AF XY: 0.176 AC XY: 127980 AN XY: 726782

Gnomad4 AFR exome AF: 0.0351

Gnomad4 AMR exome AF: 0.0891

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.0519

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.139 AC: 21106 AN: 152182 Hom.: 1936 Cov.: 32 AF XY: 0.139 AC XY: 10329 AN XY: 74374

Gnomad4 AFR AF: 0.0414

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.0500

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.120

Alfa AF: 0.170 Hom.: 5508

Bravo AF: 0.124

TwinsUK AF: 0.195 AC: 722

ALSPAC AF: 0.193 AC: 742

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.188 AC: 1619

ExAC AF: 0.153 AC: 18539

Asia WGS AF: 0.107 AC: 370 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.171

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Trimethylaminuria Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32653296, 23510775, 31240165, 28290528, 19321370, 17531949, 10479479, 11773868, 23211429, 10896299, 23791655, 23266626, 17142560, 12814961, 17584019, 11136294) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.000092	P;P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.22
Sift	Benign	0.20	T
Sift4G	Benign	0.15	T
Polyphen		0.94	P
Vest4		0.032
MPC		0.27
ClinPred		0.035	T
GERP RS		3.6
Varity_R		0.42
gMVP		0.60

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: rs2266780; hg19: chr1-171083242; COSMIC: COSV63006935; COSMIC: COSV63006935;