1-171280798-A-G

Variant names:

• chr1-171280798-A-G
• rs1661316011
• NM_001282693.2:c.640A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001282693.2(FMO1):​c.640A>G​(p.Thr214Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FMO1 NM_001282693.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• Publications: 0 publications found

Genes affected

FMO1 (HGNC:3769): (flavin containing dimethylaniline monoxygenase 1) Metabolic N-oxidation of the diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man resulting in a small subpopulation with reduced TMA N-oxidation capacity resulting in fish odor syndrome Trimethylaminuria. Three forms of the enzyme, FMO1 found in fetal liver, FMO2 found in adult liver, and FMO3 are encoded by genes clustered in the 1q23-q25 region. Flavin-containing monooxygenases are NADPH-dependent flavoenzymes that catalyzes the oxidation of soft nucleophilic heteroatom centers in drugs, pesticides, and xenobiotics. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282693.2. 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
	FMO1	NM_001282693.2	MANE Select	c.640A>G	p.Thr214Ala	missense	Exon 6 of 9	NP_001269622.1	Q01740-1
	FMO1	NM_001282692.1		c.652A>G	p.Thr218Ala	missense	Exon 5 of 8	NP_001269621.1	Q01740
	FMO1	NM_002021.3		c.640A>G	p.Thr214Ala	missense	Exon 6 of 9	NP_002012.1	Q01740-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO1	ENST00000617670.6	TSL:1 MANE Select	c.640A>G	p.Thr214Ala	missense	Exon 6 of 9	ENSP00000481732.1	Q01740-1
	FMO1	ENST00000354841.4	TSL:1	c.640A>G	p.Thr214Ala	missense	Exon 5 of 8	ENSP00000346901.4	Q01740-1
	FMO1	ENST00000367750.7	TSL:1	c.640A>G	p.Thr214Ala	missense	Exon 6 of 9	ENSP00000356724.3	Q01740-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460302 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726484

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4882

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111652

Other (OTH) AF: 0.00 AC: 0 AN: 60262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.034	D
Polyphen		0.98	D
Vest4		0.22
MutPred		0.71		Gain of sheet (P = 0.0827)
MVP		0.77
MPC		0.49
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.62
gMVP		0.71
Mutation Taster		=52/48	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: rs1661316011; hg19: chr1-171249937;