1-171282268-A-G

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.1118A>G(p.Lys373Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00258 in 1,613,910 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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 0.013 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (41 hom.)
• Consequence: FMO1 NM_001282693.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.30

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=0.0034496784).
• BP6: Variant 1-171282268-A-G is Benign according to our data. Variant chr1-171282268-A-G is described in ClinVar as [Benign]. Clinvar id is 782398.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2049/152250) while in subpopulation AFR AF= 0.0453 (1881/41544). AF 95% confidence interval is 0.0436. There are 41 homozygotes in gnomad4. There are 979 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO1	NM_001282693.2	c.1118A>G	p.Lys373Arg	missense_variant	7/9	ENST00000617670.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO1	ENST00000617670.6	c.1118A>G	p.Lys373Arg	missense_variant	7/9	1	NM_001282693.2	P1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2049 AN: 152132 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00376 AC: 937 AN: 249378 Hom.: 18 AF XY: 0.00270 AC XY: 365 AN XY: 134982

Gnomad AFR exome AF: 0.0478

Gnomad AMR exome AF: 0.00333

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: 0.000188

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00145 AC: 2117 AN: 1461660 Hom.: 41 Cov.: 31 AF XY: 0.00123 AC XY: 894 AN XY: 727132

Gnomad4 AFR exome AF: 0.0473

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000845

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.0135 AC: 2049 AN: 152250 Hom.: 41 Cov.: 32 AF XY: 0.0131 AC XY: 979 AN XY: 74454

Gnomad4 AFR AF: 0.0453

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00242 Hom.: 25

Bravo AF: 0.0154

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0483 AC: 213

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00461 AC: 560

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.021
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.72	T;.;.;T
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.38	N;.;N;N
REVEL	Benign	0.096
Sift	Benign	0.032	D;.;D;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.044	.;B;B;B
Vest4		0.12
MVP		0.71
MPC		0.19
ClinPred		0.042	T
GERP RS		6.0
Varity_R		0.13
gMVP		0.40

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: rs28360421; hg19: chr1-171251407;