1-171111474-G-C

Position:

• chr1-171111474-G-C

Variant summary

Our verdict is Benign. Variant got -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

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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.827+477G>C		intron_variant		ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.827+477G>C		intron_variant		1	NM_001002294.3	ENSP00000356729	P1
	ENST00000669750.1	n.533+56630C>G		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.0591

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.226

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.35

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: rs7061710; hg19: chr1-171080615;