chr1-171332743-T-C

Variant names:

• chr1-171332743-T-C
• rs61747501
• NM_002022.3:c.662T>C

Variant summary

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

The NM_002022.3(FMO4):​c.662T>C​(p.Leu221Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L221H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FMO4 NM_002022.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.155
• Publications: 13 publications found

Genes affected

FMO4 (HGNC:3772): (flavin containing dimethylaniline monoxygenase 4) Metabolic N-oxidation of diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man. This results in a small subpopulation with reduced TMA N-oxidation capacity and causes fish odor syndrome (Trimethylaminuria). Three forms of the enzyme 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. [provided by RefSeq, Jan 2015]

ENSG00000302209 (HGNC:):

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_002022.3. 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
	FMO4	NM_002022.3	MANE Select	c.662T>C	p.Leu221Pro	missense	Exon 7 of 10	NP_002013.1	P31512

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FMO4	ENST00000367749.4	TSL:1 MANE Select	c.662T>C	p.Leu221Pro	missense	Exon 7 of 10	ENSP00000356723.3	P31512
	FMO4	ENST00000853715.1		c.662T>C	p.Leu221Pro	missense	Exon 7 of 10	ENSP00000523774.1
	FMO4	ENST00000853716.1		c.662T>C	p.Leu221Pro	missense	Exon 8 of 11	ENSP00000523775.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.15
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.22
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.031	D
Polyphen		0.54	P
Vest4		0.45
MutPred		0.78		Gain of disorder (P = 0.0141)
MVP		0.46
MPC		0.38
ClinPred		0.84	D
GERP RS		-5.2
Varity_R		0.42
gMVP		0.78
Mutation Taster		=93/7	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: rs61747501; hg19: chr1-171301882;