chr1-171114034-C-T

Variant names:

• chr1-171114034-C-T
• rs909530
• NM_001002294.3:c.855C>T
• FMO3 p.Asn285=

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -15 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_StrongBP7

The NM_001002294.3(FMO3):c.855C>T (p.Asn285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.265 (AC=426,599) in the gnomAD database across 1,607,532 control chromosomes, including 59,493 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.439. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7980 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51513 hom.)
• Consequence: FMO3 NM_001002294.3 synonymous
• Predictors: AlphaGenome AVI: 0.3: Benign
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.534
• Publications: 48 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, PanelApp Australia, Labcorp Genetics (formerly Invitae)

FMO1-AS1 (HGNC:40240): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4393 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001002294.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FMO3 NM_001002294.3	MANE Select	c.855C>T p.Asn285=	synonymous	Exon 7 of 9	Prot: NP_001002294.1
	FMO3 NM_006894.6		c.855C>T p.Asn285=	synonymous	Exon 7 of 9	Prot: NP_008825.4
	FMO3 NM_001319173.2		c.795C>T p.Asn265=	synonymous	Exon 8 of 10	Prot: NP_001306102.1

FMO3 NM_001002294.3

MANE Select

HGVSc / HGVSpc.855C>Tp.Asn285=

Exon rankExon 7 of 9

synonymous

Prot: NP_001002294.1

FMO3 NM_006894.6

HGVSc / HGVSpc.855C>Tp.Asn285=

Exon rankExon 7 of 9

synonymous

Prot: NP_008825.4

FMO3 NM_001319173.2

HGVSc / HGVSpc.795C>Tp.Asn265=

Exon rankExon 8 of 10

synonymous

Prot: NP_001306102.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FMO3 ENST00000367755.9	MANE Select	c.855C>T p.Asn285=	synonymous	Exon 7 of 9	Prot: ENSP00000356729
	FMO1-AS1 ENST00000669750.1		n.533+54070G>A	intronnon_coding_transcript	Intron 3 of 4	Prot:
	FMO3 ENST00000896149.1		c.855C>T p.Asn285=	synonymous	Exon 7 of 9	Prot: ENSP00000566208

FMO3 ENST00000367755.9

MANE Select

HGVSc / HGVSpc.855C>Tp.Asn285=

Exon rankExon 7 of 9

synonymous

Prot: ENSP00000356729

FMO1-AS1 ENST00000669750.1

HGVSc / HGVSpn.533+54070G>A

Exon rankIntron 3 of 4

intronnon_coding_transcript

Prot:

FMO3 ENST00000896149.1

HGVSc / HGVSpc.855C>Tp.Asn285=

Exon rankExon 7 of 9

synonymous

Prot: ENSP00000566208

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.313	AC:47500	Hom:7962	AN:151874	Cov:32
GnomAD2 exomes	AF: 0.286	AC:71338	Hom:	AN:249238	Cov:
GnomAD4 exome	AF: 0.260	AC:379031	Hom:51513	AN:1455540	Cov:32
GnomAD4 genome	AF: 0.313	AC:47568	Hom:7980	AN:151992	Cov:32
TOPMed (Bravo)	AF: 0.322	AC:85191	Hom:14936	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.266	AC:155898	Hom:22425	AN:585657	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.278	AC:652	Hom:106	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.373	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.253	AC:76	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.307	AC:3999	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.329	AC:1143	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.375	AC:2714	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.203	AC:407	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.389	AC:47710	Hom:9281	AN:122750	Cov:
Turkish Variome	AF: 0.154	AC:1034	Hom:93	AN:6722	Cov:
UK10K	AF: 0.243	AC:1841	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.371	AC:3324	Hom:606	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.282 *	3122	11058	0.276 *	4846	17546
BipEx(Bipolar disorder (including schizoaffective))	0.260	7383	28384	0.261	7507	28798
Epi25(Epilepsy)	0.264	11066	41936	0.266	17774	66806
SCHEMA(Schizophrenia)	0.348	49556	142596	0.345	85942	248838

Showing 4 cohortsAllele count / allele number. *AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	2	Trimethylaminuria (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.26
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.3
DANN	Benign	0.40
GPN-Star LLR	N/A	3.3
GPN-Star score	N/A	3.3
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.53

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.050	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs909530;

hg19: chr1-171083174;

COSMIC: COSV63006769;

COSMIC: COSV63006769;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar