1-171108024-G-A

Position:

• chr1-171108024-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001002294.3(FMO3):​c.485-55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,594,058 control chromosomes in the GnomAD database, including 27,172 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 0.14 (1995 hom., cov: 33)
  • Exomes 𝑓: 0.18 (25177 hom.)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242

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]

ENSG00000231424 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.485-55G>A		intron_variant		ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.485-55G>A		intron_variant		1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.468-92G>A		intron_variant		5		ENSP00000477451.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21894 AN: 151980 Hom.: 1995 Cov.: 33

Gnomad AFR AF: 0.0593

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.0496

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.179 AC: 258261 AN: 1441960 Hom.: 25177 Cov.: 29 AF XY: 0.176 AC XY: 126174 AN XY: 718722

Gnomad4 AFR exome AF: 0.0560

Gnomad4 AMR exome AF: 0.0896

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.0518

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.144 AC: 21899 AN: 152098 Hom.: 1995 Cov.: 33 AF XY: 0.144 AC XY: 10703 AN XY: 74324

Gnomad4 AFR AF: 0.0593

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.0494

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.123

Alfa AF: 0.170 Hom.: 324

Bravo AF: 0.130

Asia WGS AF: 0.108 AC: 375 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.58

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: rs2066529; hg19: chr1-171077165; COSMIC: COSV63008505; COSMIC: COSV63008505;