chr1-171116174-A-AT

Variant names:

• chr1-171116174-A-AT
• rs397820586
• NM_001002294.3:c.1184-32dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001002294.3(FMO3):​c.1184-32dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.31 (7969 hom., cov: 0)
  • Exomes 𝑓: 0.26 (43621 hom.)
• Consequence: FMO3 NM_001002294.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21
• Publications: 2 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)

ENSG00000231424 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-171116174-A-AT is Benign according to our data. Variant chr1-171116174-A-AT is described in ClinVar as Benign. ClinVar VariationId is 260065.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	NM_001002294.3	MANE Select	c.1184-32dupT		intron	N/A	NP_001002294.1
	FMO3	NM_006894.6		c.1184-32dupT		intron	N/A	NP_008825.4
	FMO3	NM_001319173.2		c.1124-32dupT		intron	N/A	NP_001306102.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO3	ENST00000367755.9	TSL:1 MANE Select	c.1184-34_1184-33insT		intron	N/A	ENSP00000356729.4
	ENSG00000231424	ENST00000653116.1		n.542+51929_542+51930insA		intron	N/A
	ENSG00000231424	ENST00000664920.1		n.681+5575_681+5576insA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47498 AN: 151938 Hom.: 7951 Cov.: 0

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.287 AC: 71911 AN: 250132 AF XY: 0.275

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.261 AC: 317162 AN: 1214582 Hom.: 43621 Cov.: 18 AF XY: 0.258 AC XY: 159417 AN XY: 617024

African (AFR) AF: 0.446 AC: 12665 AN: 28422

American (AMR) AF: 0.383 AC: 17007 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4714 AN: 24632

East Asian (EAS) AF: 0.375 AC: 14392 AN: 38408

South Asian (SAS) AF: 0.232 AC: 18858 AN: 81184

European-Finnish (FIN) AF: 0.287 AC: 15284 AN: 53222

Middle Eastern (MID) AF: 0.143 AC: 670 AN: 4672

European-Non Finnish (NFE) AF: 0.248 AC: 220102 AN: 887482

Other (OTH) AF: 0.258 AC: 13470 AN: 52200

GnomAD4 genome AF: 0.313 AC: 47567 AN: 152056 Hom.: 7969 Cov.: 0 AF XY: 0.314 AC XY: 23315 AN XY: 74332

African (AFR) AF: 0.439 AC: 18184 AN: 41464

American (AMR) AF: 0.326 AC: 4982 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3472

East Asian (EAS) AF: 0.375 AC: 1936 AN: 5164

South Asian (SAS) AF: 0.242 AC: 1167 AN: 4822

European-Finnish (FIN) AF: 0.278 AC: 2937 AN: 10574

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16856 AN: 67972

Other (OTH) AF: 0.267 AC: 562 AN: 2106

Alfa AF: 0.259 Hom.: 1189

Bravo AF: 0.322

Asia WGS AF: 0.329 AC: 1140 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397820586; hg19: chr1-171085314;