rs1983550

chr1-171103177-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001002294.3(FMO3):c.133-608G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 152,088 control chromosomes in the GnomAD database, including 556 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 0.058 (556 hom., cov: 32)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.224

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO3	NM_001002294.3	c.133-608G>A		intron_variant		ENST00000367755.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO3	ENST00000367755.9	c.133-608G>A		intron_variant		1	NM_001002294.3	P1
	ENST00000669750.1	n.533+64927C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8735 AN: 151970 Hom.: 550 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0449

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0575 AC: 8747 AN: 152088 Hom.: 556 Cov.: 32 AF XY: 0.0627 AC XY: 4661 AN XY: 74346

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.0571

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.0321

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0457 Hom.: 46

Bravo AF: 0.0646

Asia WGS AF: 0.188 AC: 650 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.2
Dann	Benign	0.42

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: rs1983550; hg19: chr1-171072318;