rs2064076

Variant names:

• chr1-171093357-G-A
• rs2064076
• NM_001002294.3:c.132+567G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-171093357-G-A
• chr1-171093357-G-C

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+567G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 151,734 control chromosomes in the GnomAD database, including 17,044 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 (17044 hom., cov: 30)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.553
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.132+567G>A		intron_variant	Intron 2 of 8	ENST00000367755.9	NP_001002294.1
FMO3	NM_006894.6	c.132+567G>A		intron_variant	Intron 2 of 8		NP_008825.4
FMO3	NM_001319173.2	c.-56+567G>A		intron_variant	Intron 2 of 9		NP_001306102.1
FMO3	NM_001319174.2	c.132+567G>A		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+567G>A		intron_variant	Intron 2 of 8	1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.132+567G>A		intron_variant	Intron 2 of 5	5		ENSP00000477451.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71718 AN: 151616 Hom.: 17027 Cov.: 30

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.473 AC: 71777 AN: 151734 Hom.: 17044 Cov.: 30 AF XY: 0.475 AC XY: 35228 AN XY: 74140

African (AFR) AF: 0.476 AC: 19695 AN: 41342

American (AMR) AF: 0.508 AC: 7741 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1358 AN: 3468

East Asian (EAS) AF: 0.407 AC: 2088 AN: 5126

South Asian (SAS) AF: 0.515 AC: 2477 AN: 4814

European-Finnish (FIN) AF: 0.483 AC: 5079 AN: 10520

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

European-Non Finnish (NFE) AF: 0.471 AC: 31962 AN: 67912

Other (OTH) AF: 0.448 AC: 947 AN: 2114

Alfa AF: 0.445 Hom.: 3807

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	-0.99
CADD	Benign	8.3
DANN	Benign	0.56
PhyloP100		-0.55
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: rs2064076; hg19: chr1-171062498;