1-171107794-C-T

Variant names:

• chr1-171107794-C-T
• rs1800822
• NM_001002294.3:c.441C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001002294.3(FMO3):​c.441C>T​(p.Ser147Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,613,590 control chromosomes in the GnomAD database, including 7,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (798 hom., cov: 32)
  • Exomes 𝑓: 0.074 (6213 hom.)
• Consequence: FMO3 NM_001002294.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.42
• Publications: 33 publications found

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]

FMO3 Gene-Disease associations (from GenCC):

• trimethylaminuria

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• severe primary trimethylaminuria

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000231424 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-171107794-C-T is Benign according to our data. Variant chr1-171107794-C-T is described in ClinVar as Benign. ClinVar VariationId is 260073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.441C>T	p.Ser147Ser	synonymous_variant	Exon 4 of 9	ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.441C>T	p.Ser147Ser	synonymous_variant	Exon 4 of 9	1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.441C>T	p.Ser147Ser	synonymous_variant	Exon 4 of 6	5		ENSP00000477451.1

Frequencies

GnomAD3 genomes AF: 0.0843 AC: 12815 AN: 151994 Hom.: 790 Cov.: 32

Gnomad AFR AF: 0.0798

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0809

GnomAD2 exomes AF: 0.115 AC: 28765 AN: 251004 AF XY: 0.110

Gnomad AFR exome AF: 0.0795

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.0803

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0947

GnomAD4 exome AF: 0.0743 AC: 108657 AN: 1461478 Hom.: 6213 Cov.: 32 AF XY: 0.0762 AC XY: 55397 AN XY: 727040

African (AFR) AF: 0.0808 AC: 2704 AN: 33462

American (AMR) AF: 0.274 AC: 12263 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0797 AC: 2083 AN: 26120

East Asian (EAS) AF: 0.200 AC: 7934 AN: 39672

South Asian (SAS) AF: 0.175 AC: 15122 AN: 86240

European-Finnish (FIN) AF: 0.0451 AC: 2409 AN: 53418

Middle Eastern (MID) AF: 0.0947 AC: 546 AN: 5766

European-Non Finnish (NFE) AF: 0.0544 AC: 60527 AN: 1111724

Other (OTH) AF: 0.0840 AC: 5069 AN: 60372

GnomAD4 genome AF: 0.0844 AC: 12837 AN: 152112 Hom.: 798 Cov.: 32 AF XY: 0.0886 AC XY: 6589 AN XY: 74356

African (AFR) AF: 0.0798 AC: 3311 AN: 41500

American (AMR) AF: 0.191 AC: 2915 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 282 AN: 3468

East Asian (EAS) AF: 0.206 AC: 1061 AN: 5162

South Asian (SAS) AF: 0.186 AC: 892 AN: 4806

European-Finnish (FIN) AF: 0.0414 AC: 438 AN: 10588

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0533 AC: 3625 AN: 68000

Other (OTH) AF: 0.0839 AC: 177 AN: 2110

Alfa AF: 0.0690 Hom.: 2260

Bravo AF: 0.0945

Asia WGS AF: 0.197 AC: 682 AN: 3476

EpiCase AF: 0.0590

EpiControl AF: 0.0564

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Trimethylaminuria Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.9
DANN	Benign	0.56
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800822; hg19: chr1-171076935; COSMIC: COSV63006763; COSMIC: COSV63006763;