1-171111344-C-T

Position:

• chr1-171111344-C-T

Variant summary

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

The NM_001002294.3(FMO3):​c.827+347C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 151,864 control chromosomes in the GnomAD database, including 29,797 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 0.62 (29797 hom., cov: 31)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.482

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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.827+347C>T		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+347C>T		intron_variant		1	NM_001002294.3	ENSP00000356729.4

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93538 AN: 151744 Hom.: 29739 Cov.: 31

Gnomad AFR AF: 0.785

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.571

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

GnomAD4 genome AF: 0.617 AC: 93658 AN: 151864 Hom.: 29797 Cov.: 31 AF XY: 0.616 AC XY: 45746 AN XY: 74208

Gnomad4 AFR AF: 0.785

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.516

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.622

Gnomad4 FIN AF: 0.522

Gnomad4 NFE AF: 0.540

Gnomad4 OTH AF: 0.571

Alfa AF: 0.551 Hom.: 36887

Bravo AF: 0.629

Asia WGS AF: 0.594 AC: 2067 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	0.93
DANN	Benign	0.57

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: rs2075992; hg19: chr1-171080485;