rs2066530

Variant names:

• chr1-171114009-T-C
• rs2066530
• NM_001002294.3:c.830T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-171114009-T-C
• chr1-171114009-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001002294.3(FMO3):​c.830T>C​(p.Val277Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,588,188 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (48 hom.)
• Consequence: FMO3 NM_001002294.3 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.964
• Publications: 19 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=0.0020459294).
• BP6: Variant 1-171114009-T-C is Benign according to our data. Variant chr1-171114009-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0144 (2183/151840) while in subpopulation AFR AF = 0.0498 (2060/41386). AF 95% confidence interval is 0.048. There are 43 homozygotes in GnomAd4. There are 993 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

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.830T>C	p.Val277Ala	missense splice_region	Exon 7 of 9	NP_001002294.1	A0A024R8Z4
	FMO3	NM_006894.6		c.830T>C	p.Val277Ala	missense splice_region	Exon 7 of 9	NP_008825.4
	FMO3	NM_001319173.2		c.770T>C	p.Val257Ala	missense splice_region	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.830T>C	p.Val277Ala	missense splice_region	Exon 7 of 9	ENSP00000356729.4	P31513
	FMO3	ENST00000896149.1		c.830T>C	p.Val277Ala	missense splice_region	Exon 7 of 9	ENSP00000566208.1
	FMO3	ENST00000896150.1		c.830T>C	p.Val277Ala	missense splice_region	Exon 8 of 10	ENSP00000566209.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2177 AN: 151722 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00631

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00361 AC: 896 AN: 248098 AF XY: 0.00252

Gnomad AFR exome AF: 0.0487

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00135 AC: 1940 AN: 1436348 Hom.: 48 Cov.: 27 AF XY: 0.00111 AC XY: 793 AN XY: 715786

African (AFR) AF: 0.0477 AC: 1554 AN: 32606

American (AMR) AF: 0.00273 AC: 120 AN: 43952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.000106 AC: 9 AN: 85130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5704

European-Non Finnish (NFE) AF: 0.0000532 AC: 58 AN: 1090886

Other (OTH) AF: 0.00309 AC: 184 AN: 59508

GnomAD4 genome AF: 0.0144 AC: 2183 AN: 151840 Hom.: 43 Cov.: 32 AF XY: 0.0134 AC XY: 993 AN XY: 74182

African (AFR) AF: 0.0498 AC: 2060 AN: 41386

American (AMR) AF: 0.00624 AC: 95 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67938

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00501 Hom.: 60

Bravo AF: 0.0157

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0474 AC: 209

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00442 AC: 537

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Trimethylaminuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.2
DANN	Benign	0.42
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.0071	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.32	N
PhyloP100		0.96
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.029
Sift	Benign	0.56	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.039
MVP		0.22
MPC		0.048
ClinPred		0.00076	T
GERP RS		1.3
Varity_R		0.035
gMVP		0.33
Mutation Taster		=98/2	polymorphism

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: rs2066530; hg19: chr1-171083149;