1-171107747-G-C

Variant names:

• chr1-171107747-G-C
• rs12072582
• NM_001002294.3:c.394G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001002294.3(FMO3):​c.394G>C​(p.Asp132His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,613,428 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (31 hom.)
• Consequence: FMO3 NM_001002294.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0950
• Publications: 20 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)

FMO1-AS1 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051504076).
• BP6: Variant 1-171107747-G-C is Benign according to our data. Variant chr1-171107747-G-C is described in ClinVar as Benign. ClinVar VariationId is 260072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1884/152234) while in subpopulation AFR AF = 0.0438 (1820/41532). AF 95% confidence interval is 0.0421. There are 45 homozygotes in GnomAd4. There are 886 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	NM_001002294.3	MANE Select	c.394G>C	p.Asp132His	missense	Exon 4 of 9	NP_001002294.1	A0A024R8Z4
	FMO3	NM_006894.6		c.394G>C	p.Asp132His	missense	Exon 4 of 9	NP_008825.4
	FMO3	NM_001319173.2		c.334G>C	p.Asp112His	missense	Exon 5 of 10	NP_001306102.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	ENST00000367755.9	TSL:1 MANE Select	c.394G>C	p.Asp132His	missense	Exon 4 of 9	ENSP00000356729.4	P31513
	FMO3	ENST00000479749.1	TSL:5	c.394G>C	p.Asp132His	missense	Exon 4 of 6	ENSP00000477451.1	V9GZ60
	FMO3	ENST00000896149.1		c.394G>C	p.Asp132His	missense	Exon 4 of 9	ENSP00000566208.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1880 AN: 152116 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00302 AC: 758 AN: 250874 AF XY: 0.00229

Gnomad AFR exome AF: 0.0415

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00124 AC: 1815 AN: 1461194 Hom.: 31 Cov.: 31 AF XY: 0.00107 AC XY: 777 AN XY: 726926

African (AFR) AF: 0.0456 AC: 1525 AN: 33452

American (AMR) AF: 0.00181 AC: 81 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111454

Other (OTH) AF: 0.00237 AC: 143 AN: 60368

GnomAD4 genome AF: 0.0124 AC: 1884 AN: 152234 Hom.: 45 Cov.: 33 AF XY: 0.0119 AC XY: 886 AN XY: 74428

African (AFR) AF: 0.0438 AC: 1820 AN: 41532

American (AMR) AF: 0.00294 AC: 45 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00172 Hom.: 2

Bravo AF: 0.0134

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0399 AC: 176

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00351 AC: 426

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Trimethylaminuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.095
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.13
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.058	T
Polyphen		0.036	B
Vest4		0.12
MVP		0.42
MPC		0.073
ClinPred		0.036	T
GERP RS		-2.1
Varity_R		0.35
gMVP		0.51
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs12072582; hg19: chr1-171076888;