rs1920149

Positions:

• chr1-171108057-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001002294.3(FMO3):​c.485-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 1,610,230 control chromosomes in the GnomAD database, including 193,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22765 hom., cov: 32)
  • Exomes 𝑓: 0.48 (170798 hom.)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.424

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-171108057-G-A is Benign according to our data. Variant chr1-171108057-G-A is described in ClinVar as [Benign]. Clinvar id is 260074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-171108057-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.485-22G>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.485-22G>A		intron_variant		1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.468-59G>A		intron_variant		5		ENSP00000477451.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81527 AN: 151808 Hom.: 22721 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.496

GnomAD3 exomes AF: 0.500 AC: 125500 AN: 250838 Hom.: 32220 AF XY: 0.492 AC XY: 66747 AN XY: 135550

Gnomad AFR exome AF: 0.704

Gnomad AMR exome AF: 0.594

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.401

Gnomad SAS exome AF: 0.512

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.461

GnomAD4 exome AF: 0.481 AC: 700864 AN: 1458304 Hom.: 170798 Cov.: 34 AF XY: 0.480 AC XY: 348607 AN XY: 725606

Gnomad4 AFR exome AF: 0.712

Gnomad4 AMR exome AF: 0.586

Gnomad4 ASJ exome AF: 0.397

Gnomad4 EAS exome AF: 0.402

Gnomad4 SAS exome AF: 0.515

Gnomad4 FIN exome AF: 0.492

Gnomad4 NFE exome AF: 0.471

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.537 AC: 81631 AN: 151926 Hom.: 22765 Cov.: 32 AF XY: 0.537 AC XY: 39850 AN XY: 74254

Gnomad4 AFR AF: 0.701

Gnomad4 AMR AF: 0.530

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.408

Gnomad4 SAS AF: 0.515

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.471

Gnomad4 OTH AF: 0.496

Alfa AF: 0.476 Hom.: 18284

Bravo AF: 0.547

Asia WGS AF: 0.457 AC: 1590 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Trimethylaminuria Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.045
DANN	Benign	0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1920149; hg19: chr1-171077198; COSMIC: COSV63006766; COSMIC: COSV63006766;