NM_001002294.3:c.472G>A

Variant names:

• chr1-171107825-G-A
• rs2266782
• NM_001002294.3:c.472G>A

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.472G>A​(p.Glu158Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,613,236 control chromosomes in the GnomAD database, including 133,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12999 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120066 hom.)
• Consequence: FMO3 NM_001002294.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.221
• Publications: 166 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=7.8064203E-4).
• BP6: Variant 1-171107825-G-A is Benign according to our data. Variant chr1-171107825-G-A is described in ClinVar as Benign. ClinVar VariationId is 38394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

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.472G>A	p.Glu158Lys	missense	Exon 4 of 9	NP_001002294.1	A0A024R8Z4
	FMO3	NM_006894.6		c.472G>A	p.Glu158Lys	missense	Exon 4 of 9	NP_008825.4
	FMO3	NM_001319173.2		c.412G>A	p.Glu138Lys	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.472G>A	p.Glu158Lys	missense	Exon 4 of 9	ENSP00000356729.4	P31513
	FMO3	ENST00000479749.1	TSL:5	c.467+5G>A		splice_region intron	N/A	ENSP00000477451.1	V9GZ60
	FMO3	ENST00000896149.1		c.472G>A	p.Glu158Lys	missense	Exon 4 of 9	ENSP00000566208.1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61759 AN: 151854 Hom.: 12984 Cov.: 32

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.379

GnomAD2 exomes AF: 0.374 AC: 93922 AN: 251054 AF XY: 0.374

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.401 AC: 586405 AN: 1461262 Hom.: 120066 Cov.: 43 AF XY: 0.400 AC XY: 290715 AN XY: 726942

African (AFR) AF: 0.463 AC: 15501 AN: 33458

American (AMR) AF: 0.304 AC: 13589 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 8278 AN: 26120

East Asian (EAS) AF: 0.202 AC: 8023 AN: 39678

South Asian (SAS) AF: 0.339 AC: 29264 AN: 86250

European-Finnish (FIN) AF: 0.447 AC: 23850 AN: 53414

Middle Eastern (MID) AF: 0.324 AC: 1870 AN: 5766

European-Non Finnish (NFE) AF: 0.417 AC: 462955 AN: 1111504

Other (OTH) AF: 0.382 AC: 23075 AN: 60374

GnomAD4 genome AF: 0.407 AC: 61800 AN: 151974 Hom.: 12999 Cov.: 32 AF XY: 0.404 AC XY: 29988 AN XY: 74302

African (AFR) AF: 0.459 AC: 19016 AN: 41428

American (AMR) AF: 0.325 AC: 4960 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1091 AN: 3472

East Asian (EAS) AF: 0.202 AC: 1046 AN: 5174

South Asian (SAS) AF: 0.331 AC: 1591 AN: 4812

European-Finnish (FIN) AF: 0.440 AC: 4647 AN: 10566

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28360 AN: 67948

Other (OTH) AF: 0.376 AC: 795 AN: 2112

Alfa AF: 0.404 Hom.: 63670

Bravo AF: 0.400

TwinsUK AF: 0.408 AC: 1512

ALSPAC AF: 0.417 AC: 1609

ESP6500AA AF: 0.465 AC: 2050

ESP6500EA AF: 0.410 AC: 3530

ExAC AF: 0.383 AC: 46481

Asia WGS AF: 0.243 AC: 847 AN: 3478

EpiCase AF: 0.394

EpiControl AF: 0.396

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	3	Trimethylaminuria (3)
-	-	1	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.00078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.22
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.56	T
Sift4G	Benign	0.47	T
Polyphen		0.0060	B
Vest4		0.042
MPC		0.067
ClinPred		0.0062	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.30
Mutation Taster		=98/2	polymorphism (auto)

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: rs2266782; hg19: chr1-171076966; COSMIC: COSV63006313; COSMIC: COSV63006313;