rs1736557

Variant names:

• chr1-171110939-G-A
• rs1736557
• NM_001002294.3:c.769G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-171110939-G-A
• chr1-171110939-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001002294.3(FMO3):​c.769G>A​(p.Val257Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,613,770 control chromosomes in the GnomAD database, including 5,296 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (407 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4889 hom.)
• Consequence: FMO3 NM_001002294.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: -1.35
• Publications: 104 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)

FMO1-AS1 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024797022).
• BP6: Variant 1-171110939-G-A is Benign according to our data. Variant chr1-171110939-G-A is described in ClinVar as Benign. ClinVar VariationId is 16305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	NM_001002294.3	MANE Select	c.769G>A	p.Val257Met	missense	Exon 6 of 9	NP_001002294.1	A0A024R8Z4
	FMO3	NM_006894.6		c.769G>A	p.Val257Met	missense	Exon 6 of 9	NP_008825.4
	FMO3	NM_001319173.2		c.709G>A	p.Val237Met	missense	Exon 7 of 10	NP_001306102.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	ENST00000367755.9	TSL:1 MANE Select	c.769G>A	p.Val257Met	missense	Exon 6 of 9	ENSP00000356729.4	P31513
	FMO3	ENST00000896149.1		c.769G>A	p.Val257Met	missense	Exon 6 of 9	ENSP00000566208.1
	FMO3	ENST00000896150.1		c.769G>A	p.Val257Met	missense	Exon 7 of 10	ENSP00000566209.1

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9948 AN: 152106 Hom.: 405 Cov.: 32

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0803

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0692

Gnomad OTH AF: 0.0703

GnomAD2 exomes AF: 0.0815 AC: 20473 AN: 251052 AF XY: 0.0819

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.0871

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.0422

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.0772

GnomAD4 exome AF: 0.0758 AC: 110765 AN: 1461546 Hom.: 4889 Cov.: 32 AF XY: 0.0760 AC XY: 55230 AN XY: 727094

African (AFR) AF: 0.0350 AC: 1172 AN: 33458

American (AMR) AF: 0.0865 AC: 3867 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2809 AN: 26126

East Asian (EAS) AF: 0.185 AC: 7338 AN: 39688

South Asian (SAS) AF: 0.0929 AC: 8017 AN: 86254

European-Finnish (FIN) AF: 0.0439 AC: 2343 AN: 53420

Middle Eastern (MID) AF: 0.0962 AC: 554 AN: 5758

European-Non Finnish (NFE) AF: 0.0721 AC: 80173 AN: 1111758

Other (OTH) AF: 0.0744 AC: 4492 AN: 60380

GnomAD4 genome AF: 0.0654 AC: 9958 AN: 152224 Hom.: 407 Cov.: 32 AF XY: 0.0662 AC XY: 4930 AN XY: 74416

African (AFR) AF: 0.0365 AC: 1517 AN: 41568

American (AMR) AF: 0.0811 AC: 1239 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.186 AC: 957 AN: 5154

South Asian (SAS) AF: 0.107 AC: 514 AN: 4822

European-Finnish (FIN) AF: 0.0386 AC: 409 AN: 10596

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0693 AC: 4710 AN: 68014

Other (OTH) AF: 0.0696 AC: 147 AN: 2112

Alfa AF: 0.0715 Hom.: 2237

Bravo AF: 0.0659

TwinsUK AF: 0.0750 AC: 278

ALSPAC AF: 0.0714 AC: 275

ESP6500AA AF: 0.0372 AC: 164

ESP6500EA AF: 0.0693 AC: 596

ExAC AF: 0.0805 AC: 9773

Asia WGS AF: 0.136 AC: 472 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0688

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	2	Trimethylaminuria (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.97
DANN	Benign	0.87
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.052	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N
PhyloP100		-1.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.049
Sift	Benign	0.075	T
Sift4G	Benign	0.063	T
Polyphen		0.0020	B
Vest4		0.0050
MPC		0.045
ClinPred		0.0062	T
GERP RS		-9.2
Varity_R		0.042
gMVP		0.28
Mutation Taster		=99/1	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: rs1736557; hg19: chr1-171080080; COSMIC: COSV63006750; COSMIC: COSV63006750;