1-171114339-G-T

Variant names:

• chr1-171114339-G-T
• rs72549331
• NM_001002294.3:c.1160G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001002294.3(FMO3):​c.1160G>T​(p.Arg387Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R387H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FMO3 NM_001002294.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.52
• Publications: 13 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-171114339-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 427174.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 1-171114339-G-T is Pathogenic according to our data. Variant chr1-171114339-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16311.

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.1160G>T	p.Arg387Leu	missense	Exon 7 of 9	NP_001002294.1	A0A024R8Z4
	FMO3	NM_006894.6		c.1160G>T	p.Arg387Leu	missense	Exon 7 of 9	NP_008825.4
	FMO3	NM_001319173.2		c.1100G>T	p.Arg367Leu	missense	Exon 8 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.1160G>T	p.Arg387Leu	missense	Exon 7 of 9	ENSP00000356729.4	P31513
	FMO3	ENST00000896149.1		c.1160G>T	p.Arg387Leu	missense	Exon 7 of 9	ENSP00000566208.1
	FMO3	ENST00000896150.1		c.1160G>T	p.Arg387Leu	missense	Exon 8 of 10	ENSP00000566209.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 246470 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460998 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726800

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111462

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000442 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	FMO3-related disorder (1)
-	1	-	not specified (1)
1	-	-	Trimethylaminuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.5
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.98		Loss of MoRF binding (P = 0.0124)
MVP		0.76
MPC		0.31
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.90
gMVP		0.90
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72549331; hg19: chr1-171083479;