rs12404218

Variant names:

• chr1-171090116-T-A
• rs12404218
• ENST00000896149.1:c.-6-2537T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000896149.1(FMO3):​c.-6-2537T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,248 control chromosomes in the GnomAD database, including 1,073 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 0.10 (1073 hom., cov: 32)
• Consequence: FMO3 ENST00000896149.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 4 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)

FMO1-AS1 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000896149.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	ENST00000896149.1		c.-6-2537T>A		intron	N/A	ENSP00000566208.1
	FMO1-AS1	ENST00000653116.1		n.542+77988A>T		intron	N/A
	FMO1-AS1	ENST00000664920.1		n.681+31634A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15674 AN: 152130 Hom.: 1065 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.0989

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

GnomAD4 genome AF: 0.103 AC: 15700 AN: 152248 Hom.: 1073 Cov.: 32 AF XY: 0.106 AC XY: 7888 AN XY: 74462

African (AFR) AF: 0.124 AC: 5155 AN: 41534

American (AMR) AF: 0.203 AC: 3104 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 284 AN: 3470

East Asian (EAS) AF: 0.215 AC: 1113 AN: 5174

South Asian (SAS) AF: 0.194 AC: 935 AN: 4822

European-Finnish (FIN) AF: 0.0497 AC: 528 AN: 10618

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0622 AC: 4228 AN: 68016

Other (OTH) AF: 0.102 AC: 215 AN: 2116

Alfa AF: 0.0841 Hom.: 87

Bravo AF: 0.114

Asia WGS AF: 0.218 AC: 756 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
DANN	Benign	0.74
PhyloP100		0.24

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12404218; hg19: chr1-171059257;