Genetic Variant NM_001002294.3:c.1183+35T>C (chr1-171114397-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001002294.3(FMO3):c.1183+35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,419,972 control chromosomes in the GnomAD database, including 30,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4675 hom., cov: 32)

Exomes 𝑓: 0.19 ( 25353 hom. )

Consequence

FMO3
NM_001002294.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0140

Variant links:

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 links:

ENSG00000231424 (HGNC:40240):

ENSG00000231424 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-171114397-T-C is Benign according to our data. Variant chr1-171114397-T-C is described in ClinVar as [Benign]. Clinvar id is 260064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO3	NM_001002294.3 link	c.1183+35T>C		intron_variant	Intron 7 of 8	ENST00000367755.9	NP_001002294.1	P31513A0A024R8Z4Q53FW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO3	ENST00000367755.9 link	c.1183+35T>C		intron_variant	Intron 7 of 8	1	NM_001002294.3	ENSP00000356729.4		P31513

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35134

AN:

151958

Hom.:

4663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.362

Gnomad AMI

AF:

0.137

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.0520

Gnomad FIN

AF:

0.237

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.198

Gnomad OTH

AF:

0.193

GnomAD3 exomes

AF:

0.178

AC:

38530

AN:

216176

Hom.:

3940

AF XY:

0.171

AC XY:

20111

AN XY:

117398

show subpopulations

Gnomad AFR exome

AF:

0.374

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.187

Gnomad SAS exome

AF:

0.0514

Gnomad FIN exome

AF:

0.243

Gnomad NFE exome

AF:

0.204

Gnomad OTH exome

AF:

0.156

GnomAD4 exome

AF:

0.194

AC:

246086

AN:

1267896

Hom.:

25353

Cov.:

AF XY:

0.189

AC XY:

120455

AN XY:

638610

show subpopulations

Gnomad4 AFR exome

AF:

0.373

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.120

Gnomad4 EAS exome

AF:

0.187

Gnomad4 SAS exome

AF:

0.0542

Gnomad4 FIN exome

AF:

0.245

Gnomad4 NFE exome

AF:

0.205

Gnomad4 OTH exome

AF:

0.181

GnomAD4 genome

AF:

0.231

AC:

35183

AN:

152076

Hom.:

4675

Cov.:

AF XY:

0.228

AC XY:

16956

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.362

Gnomad4 AMR

AF:

0.136

Gnomad4 ASJ

AF:

0.117

Gnomad4 EAS

AF:

0.182

Gnomad4 SAS

AF:

0.0516

Gnomad4 FIN

AF:

0.237

Gnomad4 NFE

AF:

0.198

Gnomad4 OTH

AF:

0.192

Alfa

AF:

0.199

Hom.:

1490

Bravo

AF:

0.230

Asia WGS

AF:

0.131

AC:

454

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.0

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over