1-171280832-T-C

Variant names:

• chr1-171280832-T-C
• rs779933682
• NM_001282693.2:c.674T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001282693.2(FMO1):​c.674T>C​(p.Phe225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FMO1 NM_001282693.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.84

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041426152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO1	NM_001282693.2	c.674T>C	p.Phe225Ser	missense_variant	Exon 6 of 9	ENST00000617670.6	NP_001269622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO1	ENST00000617670.6	c.674T>C	p.Phe225Ser	missense_variant	Exon 6 of 9	1	NM_001282693.2	ENSP00000481732.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251290 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.674T>C (p.F225S) alteration is located in exon 6 (coding exon 5) of the FMO1 gene. This alteration results from a T to C substitution at nucleotide position 674, causing the phenylalanine (F) at amino acid position 225 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.8
DANN	Benign	0.94
DEOGEN2	Benign	0.012	.;T;T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.48	T;.;.;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.041	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	.;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.23	N;.;N;N
REVEL	Benign	0.043
Sift	Benign	0.71	T;.;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0030	.;B;B;B
Vest4		0.11
MutPred		0.55		.;Loss of stability (P = 0.0141);Loss of stability (P = 0.0141);Loss of stability (P = 0.0141);
MVP		0.21
MPC		0.22
ClinPred		0.13	T
GERP RS		-0.73
Varity_R		0.064
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs779933682; hg19: chr1-171249971;