1-171114034-C-T

Variant names:

• chr1-171114034-C-T
• rs909530
• NM_001002294.3:c.855C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001002294.3(FMO3):​c.855C>T​(p.Asn285Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,607,532 control chromosomes in the GnomAD database, including 59,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7980 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51513 hom.)
• Consequence: FMO3 NM_001002294.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.534
• Publications: 45 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-171114034-C-T is Benign according to our data. Variant chr1-171114034-C-T is described in ClinVar as Benign. ClinVar VariationId is 260078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.534 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.855C>T	p.Asn285Asn	synonymous_variant	Exon 7 of 9	ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.855C>T	p.Asn285Asn	synonymous_variant	Exon 7 of 9	1	NM_001002294.3	ENSP00000356729.4

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47500 AN: 151874 Hom.: 7962 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.286 AC: 71338 AN: 249238 AF XY: 0.274

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.366

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.260 AC: 379031 AN: 1455540 Hom.: 51513 Cov.: 32 AF XY: 0.258 AC XY: 186567 AN XY: 724140

African (AFR) AF: 0.445 AC: 14796 AN: 33228

American (AMR) AF: 0.381 AC: 16905 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4947 AN: 25976

East Asian (EAS) AF: 0.374 AC: 14828 AN: 39636

South Asian (SAS) AF: 0.232 AC: 19952 AN: 85834

European-Finnish (FIN) AF: 0.287 AC: 15304 AN: 53312

Middle Eastern (MID) AF: 0.148 AC: 851 AN: 5746

European-Non Finnish (NFE) AF: 0.249 AC: 275911 AN: 1107358

Other (OTH) AF: 0.258 AC: 15537 AN: 60128

GnomAD4 genome AF: 0.313 AC: 47568 AN: 151992 Hom.: 7980 Cov.: 32 AF XY: 0.314 AC XY: 23316 AN XY: 74286

African (AFR) AF: 0.439 AC: 18173 AN: 41442

American (AMR) AF: 0.326 AC: 4984 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3468

East Asian (EAS) AF: 0.375 AC: 1939 AN: 5168

South Asian (SAS) AF: 0.242 AC: 1167 AN: 4818

European-Finnish (FIN) AF: 0.278 AC: 2929 AN: 10550

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16871 AN: 67968

Other (OTH) AF: 0.268 AC: 564 AN: 2108

Alfa AF: 0.264 Hom.: 20848

Bravo AF: 0.322

Asia WGS AF: 0.329 AC: 1143 AN: 3478

EpiCase AF: 0.224

EpiControl AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Trimethylaminuria Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.41
CADD	Benign	5.3
DANN	Benign	0.40
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs909530; hg19: chr1-171083174; COSMIC: COSV63006769; COSMIC: COSV63006769;