rs1983550

Variant names:

• chr1-171103177-G-A
• rs1983550
• NM_001002294.3:c.133-608G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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=-0.87).
• 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 rank	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.133-608G>A		intron_variant	Intron 2 of 8	ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.133-608G>A		intron_variant	Intron 2 of 8	1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.133-608G>A		intron_variant	Intron 2 of 5	5		ENSP00000477451.1

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

African (AFR) AF: 0.0332 AC: 1376 AN: 41498

American (AMR) AF: 0.169 AC: 2578 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 198 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1062 AN: 5162

South Asian (SAS) AF: 0.177 AC: 853 AN: 4812

European-Finnish (FIN) AF: 0.0321 AC: 340 AN: 10588

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0325 AC: 2207 AN: 67988

Other (OTH) AF: 0.0468 AC: 99 AN: 2114

Alfa AF: 0.0581 Hom.: 188

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
PhyloP100		0.22
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: rs1983550; hg19: chr1-171072318;