rs2064074

chr1-171092849-A-Gchr1-171092849-A-T

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
FMO3	NM_001002294.3	c.132+59A>G		intron_variant		ENST00000367755.9
FMO3	NM_001319173.2	c.-56+59A>G		intron_variant
FMO3	NM_001319174.2	c.132+59A>G		intron_variant
FMO3	NM_006894.6	c.132+59A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO3	ENST00000367755.9	c.132+59A>G		intron_variant		1	NM_001002294.3	P1
	ENST00000669750.1	n.533+75255T>C		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.477

Gnomad4 AMR exome AF: 0.575

Gnomad4 ASJ exome AF: 0.394

Gnomad4 EAS exome AF: 0.402

Gnomad4 SAS exome AF: 0.515

Gnomad4 FIN exome AF: 0.492

Gnomad4 NFE exome AF: 0.472

Gnomad4 OTH exome AF: 0.463

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

Gnomad4 AFR AF: 0.476

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.392

Gnomad4 EAS AF: 0.405

Gnomad4 SAS AF: 0.515

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.471

Gnomad4 OTH AF: 0.448

Alfa AF: 0.437 Hom.: 8335

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2064074; hg19: chr1-171061990; COSMIC: COSV63006760;