rs2064074

Variant names:

• chr1-171092849-A-G
• rs2064074
• NM_001002294.3:c.132+59A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-171092849-A-G
• chr1-171092849-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001002294.3(FMO3):​c.132+59A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 1,572,960 control chromosomes in the GnomAD database, including 178,000 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (17050 hom., cov: 32)
  • Exomes 𝑓: 0.47 (160950 hom.)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.544
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.132+59A>G		intron_variant	Intron 2 of 8	ENST00000367755.9	NP_001002294.1
FMO3	NM_006894.6	c.132+59A>G		intron_variant	Intron 2 of 8		NP_008825.4
FMO3	NM_001319173.2	c.-56+59A>G		intron_variant	Intron 2 of 9		NP_001306102.1
FMO3	NM_001319174.2	c.132+59A>G		intron_variant	Intron 2 of 7		NP_001306103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.132+59A>G		intron_variant	Intron 2 of 8	1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.132+59A>G		intron_variant	Intron 2 of 5	5		ENSP00000477451.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71765 AN: 151856 Hom.: 17033 Cov.: 32

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.447

GnomAD4 exome AF: 0.475 AC: 674406 AN: 1420986 Hom.: 160950 AF XY: 0.475 AC XY: 336800 AN XY: 708400

African (AFR) AF: 0.477 AC: 15586 AN: 32668

American (AMR) AF: 0.575 AC: 25115 AN: 43674

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 10172 AN: 25828

East Asian (EAS) AF: 0.402 AC: 15823 AN: 39326

South Asian (SAS) AF: 0.515 AC: 43791 AN: 85040

European-Finnish (FIN) AF: 0.492 AC: 25706 AN: 52270

Middle Eastern (MID) AF: 0.424 AC: 1879 AN: 4430

European-Non Finnish (NFE) AF: 0.472 AC: 509058 AN: 1078812

Other (OTH) AF: 0.463 AC: 27276 AN: 58938

GnomAD4 genome AF: 0.473 AC: 71824 AN: 151974 Hom.: 17050 Cov.: 32 AF XY: 0.474 AC XY: 35242 AN XY: 74272

African (AFR) AF: 0.476 AC: 19719 AN: 41448

American (AMR) AF: 0.508 AC: 7753 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1357 AN: 3464

East Asian (EAS) AF: 0.405 AC: 2080 AN: 5140

South Asian (SAS) AF: 0.515 AC: 2481 AN: 4822

European-Finnish (FIN) AF: 0.481 AC: 5082 AN: 10556

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.471 AC: 31975 AN: 67952

Other (OTH) AF: 0.448 AC: 947 AN: 2116

Alfa AF: 0.440 Hom.: 11573

Bravo AF: 0.474

Asia WGS AF: 0.437 AC: 1519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.072
DANN	Benign	0.40
PhyloP100		-0.54
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: rs2064074; hg19: chr1-171061990; COSMIC: COSV63006760;