chr1-171091067-G-A

Position:

• chr1-171091067-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.-7+86G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 151,722 control chromosomes in the GnomAD database, including 29,308 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 0.61 (29308 hom., cov: 30)
  • Exomes 𝑓: 0.61 (10 hom.)
  • Failed GnomAD Quality Control
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.836

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.-7+86G>A		intron_variant		ENST00000367755.9	NP_001002294.1
FMO3	NM_006894.6	c.-7+103G>A		intron_variant			NP_008825.4
FMO3	NM_001319173.2	c.-194+103G>A		intron_variant			NP_001306102.1
FMO3	NM_001319174.2	c.-7+86G>A		intron_variant			NP_001306103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.-7+86G>A		intron_variant		1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.-7+86G>A		intron_variant		5		ENSP00000477451.1

Frequencies

GnomAD3 genomes AF: 0.614 AC: 93062 AN: 151604 Hom.: 29250 Cov.: 30

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.573

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.606 AC: 40 AN: 66 Hom.: 10 AF XY: 0.620 AC XY: 31 AN XY: 50

Gnomad4 NFE exome AF: 0.606

GnomAD4 genome AF: 0.614 AC: 93181 AN: 151722 Hom.: 29308 Cov.: 30 AF XY: 0.613 AC XY: 45474 AN XY: 74152

Gnomad4 AFR AF: 0.769

Gnomad4 AMR AF: 0.616

Gnomad4 ASJ AF: 0.517

Gnomad4 EAS AF: 0.596

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.522

Gnomad4 NFE AF: 0.546

Gnomad4 OTH AF: 0.573

Alfa AF: 0.581 Hom.: 3119

Bravo AF: 0.626

Asia WGS AF: 0.585 AC: 2035 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.64
DANN	Benign	0.69

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: rs1736561; hg19: chr1-171060208;