1-171091067-G-A

Variant names:

• chr1-171091067-G-A
• rs1736561
• NM_001002294.3:c.-7+86G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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)

ENSG00000231424 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002294.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	NM_001002294.3	MANE Select	c.-7+86G>A		intron	N/A	NP_001002294.1
	FMO3	NM_006894.6		c.-7+103G>A		intron	N/A	NP_008825.4
	FMO3	NM_001319173.2		c.-194+103G>A		intron	N/A	NP_001306102.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	ENST00000367755.9	TSL:1 MANE Select	c.-7+86G>A		intron	N/A	ENSP00000356729.4
	FMO3	ENST00000479749.1	TSL:5	c.-7+86G>A		intron	N/A	ENSP00000477451.1
	FMO3	ENST00000534514.1	TSL:1	n.77+86G>A		intron	N/A

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.606 AC: 40 AN: 66

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.769 AC: 31837 AN: 41402

American (AMR) AF: 0.616 AC: 9398 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1792 AN: 3468

East Asian (EAS) AF: 0.596 AC: 3056 AN: 5126

South Asian (SAS) AF: 0.597 AC: 2864 AN: 4796

European-Finnish (FIN) AF: 0.522 AC: 5472 AN: 10490

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37050 AN: 67868

Other (OTH) AF: 0.573 AC: 1208 AN: 2110

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.64
DANN	Benign	0.69
PhyloP100		-0.84
PromoterAI		0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1736561; hg19: chr1-171060208;