1-171102742-A-C

Variant names:

• chr1-171102742-A-C
• rs10911192
• NM_001002294.3:c.133-1043A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001002294.3(FMO3):​c.133-1043A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 151,996 control chromosomes in the GnomAD database, including 23,180 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 0.54 (23180 hom., cov: 33)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.981
• Publications: 9 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.707 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.133-1043A>C		intron	N/A	NP_001002294.1
	FMO3	NM_006894.6		c.133-1043A>C		intron	N/A	NP_008825.4
	FMO3	NM_001319173.2		c.73-1043A>C		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.133-1043A>C		intron	N/A	ENSP00000356729.4
	FMO3	ENST00000479749.1	TSL:5	c.133-1043A>C		intron	N/A	ENSP00000477451.1
	FMO3	ENST00000472784.5	TSL:5	n.*113-1043A>C		intron	N/A	ENSP00000476963.1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82206 AN: 151878 Hom.: 23136 Cov.: 33

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.542 AC: 82309 AN: 151996 Hom.: 23180 Cov.: 33 AF XY: 0.541 AC XY: 40156 AN XY: 74294

African (AFR) AF: 0.714 AC: 29621 AN: 41474

American (AMR) AF: 0.531 AC: 8117 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1373 AN: 3470

East Asian (EAS) AF: 0.408 AC: 2107 AN: 5158

South Asian (SAS) AF: 0.516 AC: 2490 AN: 4824

European-Finnish (FIN) AF: 0.482 AC: 5091 AN: 10560

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32023 AN: 67928

Other (OTH) AF: 0.500 AC: 1052 AN: 2106

Alfa AF: 0.486 Hom.: 22090

Bravo AF: 0.551

Asia WGS AF: 0.456 AC: 1588 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.75
DANN	Benign	0.60
PhyloP100		-0.98
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: rs10911192; hg19: chr1-171071883;