rs909531

Variant names:

• chr1-171114397-T-C
• rs909531
• NM_001002294.3:c.1183+35T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001002294.3(FMO3):​c.1183+35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,419,972 control chromosomes in the GnomAD database, including 30,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4675 hom., cov: 32)
  • Exomes 𝑓: 0.19 (25353 hom.)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0140
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-171114397-T-C is Benign according to our data. Variant chr1-171114397-T-C is described in ClinVar as Benign. ClinVar VariationId is 260064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.1183+35T>C		intron_variant	Intron 7 of 8	ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.1183+35T>C		intron_variant	Intron 7 of 8	1	NM_001002294.3	ENSP00000356729.4

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35134 AN: 151958 Hom.: 4663 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.193

GnomAD2 exomes AF: 0.178 AC: 38530 AN: 216176 AF XY: 0.171

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.194 AC: 246086 AN: 1267896 Hom.: 25353 Cov.: 18 AF XY: 0.189 AC XY: 120455 AN XY: 638610

African (AFR) AF: 0.373 AC: 11169 AN: 29964

American (AMR) AF: 0.109 AC: 4557 AN: 41968

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 2964 AN: 24674

East Asian (EAS) AF: 0.187 AC: 7156 AN: 38166

South Asian (SAS) AF: 0.0542 AC: 4368 AN: 80632

European-Finnish (FIN) AF: 0.245 AC: 12729 AN: 51946

Middle Eastern (MID) AF: 0.0620 AC: 331 AN: 5342

European-Non Finnish (NFE) AF: 0.205 AC: 193075 AN: 941356

Other (OTH) AF: 0.181 AC: 9737 AN: 53848

GnomAD4 genome AF: 0.231 AC: 35183 AN: 152076 Hom.: 4675 Cov.: 32 AF XY: 0.228 AC XY: 16956 AN XY: 74348

African (AFR) AF: 0.362 AC: 14997 AN: 41468

American (AMR) AF: 0.136 AC: 2083 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3472

East Asian (EAS) AF: 0.182 AC: 942 AN: 5164

South Asian (SAS) AF: 0.0516 AC: 249 AN: 4824

European-Finnish (FIN) AF: 0.237 AC: 2509 AN: 10580

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13452 AN: 67978

Other (OTH) AF: 0.192 AC: 404 AN: 2104

Alfa AF: 0.202 Hom.: 1782

Bravo AF: 0.230

Asia WGS AF: 0.131 AC: 454 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.65
PhyloP100		-0.014
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs909531; hg19: chr1-171083537; COSMIC: COSV63008509; COSMIC: COSV63008509;