rs2066529

Variant names:

• chr1-171108024-G-A
• rs2066529
• NM_001002294.3:c.485-55G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-171108024-G-A
• chr1-171108024-G-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.485-55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,594,058 control chromosomes in the GnomAD database, including 27,172 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 0.14 (1995 hom., cov: 33)
  • Exomes 𝑓: 0.18 (25177 hom.)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 8 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3	c.485-55G>A		intron_variant	Intron 4 of 8	ENST00000367755.9	NP_001002294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9	c.485-55G>A		intron_variant	Intron 4 of 8	1	NM_001002294.3	ENSP00000356729.4
FMO3	ENST00000479749.1	c.468-92G>A		intron_variant	Intron 4 of 5	5		ENSP00000477451.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21894 AN: 151980 Hom.: 1995 Cov.: 33

Gnomad AFR AF: 0.0593

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.0496

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.179 AC: 258261 AN: 1441960 Hom.: 25177 Cov.: 29 AF XY: 0.176 AC XY: 126174 AN XY: 718722

African (AFR) AF: 0.0560 AC: 1844 AN: 32912

American (AMR) AF: 0.0896 AC: 4000 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2939 AN: 26020

East Asian (EAS) AF: 0.185 AC: 7325 AN: 39606

South Asian (SAS) AF: 0.0518 AC: 4441 AN: 85756

European-Finnish (FIN) AF: 0.243 AC: 12988 AN: 53376

Middle Eastern (MID) AF: 0.0459 AC: 263 AN: 5724

European-Non Finnish (NFE) AF: 0.197 AC: 215185 AN: 1094202

Other (OTH) AF: 0.155 AC: 9276 AN: 59714

GnomAD4 genome AF: 0.144 AC: 21899 AN: 152098 Hom.: 1995 Cov.: 33 AF XY: 0.144 AC XY: 10703 AN XY: 74324

African (AFR) AF: 0.0593 AC: 2461 AN: 41518

American (AMR) AF: 0.103 AC: 1568 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3472

East Asian (EAS) AF: 0.182 AC: 946 AN: 5184

South Asian (SAS) AF: 0.0494 AC: 238 AN: 4814

European-Finnish (FIN) AF: 0.237 AC: 2501 AN: 10536

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13402 AN: 67982

Other (OTH) AF: 0.123 AC: 259 AN: 2112

Alfa AF: 0.170 Hom.: 324

Bravo AF: 0.130

Asia WGS AF: 0.108 AC: 375 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.58
PhyloP100		0.24
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: rs2066529; hg19: chr1-171077165; COSMIC: COSV63008505; COSMIC: COSV63008505;