chr1-171111474-G-C

Variant names:

• chr1-171111474-G-C
• rs7061710
• NM_001002294.3:c.827+477G>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.827+477G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,010 control chromosomes in the GnomAD database, including 5,781 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 0.26 (5781 hom., cov: 32)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.487
• Publications: 13 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002294.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	NM_001002294.3	MANE Select	c.827+477G>C		intron	N/A	NP_001002294.1
	FMO3	NM_006894.6		c.827+477G>C		intron	N/A	NP_008825.4
	FMO3	NM_001319173.2		c.767+477G>C		intron	N/A	NP_001306102.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	ENST00000367755.9	TSL:1 MANE Select	c.827+477G>C		intron	N/A	ENSP00000356729.4
	ENSG00000231424	ENST00000653116.1		n.542+56630C>G		intron	N/A
	ENSG00000231424	ENST00000664920.1		n.681+10276C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38971 AN: 151892 Hom.: 5765 Cov.: 32

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0593

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.257 AC: 39035 AN: 152010 Hom.: 5781 Cov.: 32 AF XY: 0.253 AC XY: 18783 AN XY: 74298

African (AFR) AF: 0.405 AC: 16767 AN: 41430

American (AMR) AF: 0.156 AC: 2391 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3470

East Asian (EAS) AF: 0.183 AC: 948 AN: 5176

South Asian (SAS) AF: 0.0591 AC: 285 AN: 4820

European-Finnish (FIN) AF: 0.247 AC: 2606 AN: 10562

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14846 AN: 67950

Other (OTH) AF: 0.226 AC: 478 AN: 2114

Alfa AF: 0.243 Hom.: 612

Bravo AF: 0.258

Asia WGS AF: 0.141 AC: 488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.35
PhyloP100		-0.49
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: rs7061710; hg19: chr1-171080615;