1-171282129-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001282693.2(FMO1):c.979T>C(p.Phe327Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,036 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0062 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (14 hom.)
• Consequence: FMO1 NM_001282693.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.01

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011241078).
• BP6: Variant 1-171282129-T-C is Benign according to our data. Variant chr1-171282129-T-C is described in ClinVar as [Benign]. Clinvar id is 782397.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00623 (949/152334) while in subpopulation AFR AF= 0.0203 (845/41570). AF 95% confidence interval is 0.0192. There are 13 homozygotes in gnomad4. There are 441 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO1	NM_001282693.2	c.979T>C	p.Phe327Leu	missense_variant	7/9	ENST00000617670.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO1	ENST00000617670.6	c.979T>C	p.Phe327Leu	missense_variant	7/9	1	NM_001282693.2	P1

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 948 AN: 152216 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00186 AC: 468 AN: 251316 Hom.: 5 AF XY: 0.00128 AC XY: 174 AN XY: 135830

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000731 AC: 1069 AN: 1461702 Hom.: 14 Cov.: 31 AF XY: 0.000597 AC XY: 434 AN XY: 727160

Gnomad4 AFR exome AF: 0.0208

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00623 AC: 949 AN: 152334 Hom.: 13 Cov.: 32 AF XY: 0.00592 AC XY: 441 AN XY: 74500

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00144 Hom.: 1

Bravo AF: 0.00765

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00227 AC: 276

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T;.;.;D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.2	D;.;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.31
MutPred		0.28		.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.86
MPC		0.61
ClinPred		0.035	T
GERP RS		6.0
Varity_R		0.70
gMVP		0.71

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: rs28360420; hg19: chr1-171251268;