rs144935285

Variant names:

• chr1-171103824-G-A
• rs144935285
• NM_001002294.3:c.172G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP5 BP4 BS1_Supporting

The NM_006894.6(FMO3):​c.172G>A​(p.Val58Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: FMO3 NM_006894.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 1.26
• 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)

FMO1-AS1 (HGNC:40240):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_006894.6
• PP5: Variant 1-171103824-G-A is Pathogenic according to our data. Variant chr1-171103824-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225365.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009486079). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00023 (35/152206) while in subpopulation EAS AF = 0.00504 (26/5160). AF 95% confidence interval is 0.00353. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006894.6. 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.172G>A	p.Val58Ile	missense	Exon 3 of 9	NP_001002294.1
	FMO3	NM_006894.6		c.172G>A	p.Val58Ile	missense	Exon 3 of 9	NP_008825.4
	FMO3	NM_001319173.2		c.112G>A	p.Val38Ile	missense	Exon 4 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.172G>A	p.Val58Ile	missense	Exon 3 of 9	ENSP00000356729.4
	FMO3	ENST00000479749.1	TSL:5	c.172G>A	p.Val58Ile	missense	Exon 3 of 6	ENSP00000477451.1
	FMO3	ENST00000896149.1		c.172G>A	p.Val58Ile	missense	Exon 3 of 9	ENSP00000566208.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000346 AC: 87 AN: 251230 AF XY: 0.000331

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00419

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1461688 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00333 AC: 132 AN: 39686

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111878

Other (OTH) AF: 0.000298 AC: 18 AN: 60392

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74426

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00504 AC: 26 AN: 5160

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Trimethylaminuria (5)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.27
Sift	Uncertain	0.022	D
Sift4G	Benign	0.11	T
Polyphen		0.50	P
Vest4		0.69
MVP		0.47
MPC		0.21
ClinPred		0.27	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.38
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs144935285; hg19: chr1-171072965;