rs12720462

Variant names:

• chr1-171248552-C-A
• rs12720462
• NM_001282693.2:c.-78C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001282693.2(FMO1):​c.-78C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,252 control chromosomes in the GnomAD database, including 1,154 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1153 hom., cov: 31)
  • Exomes 𝑓: 0.75 (1 hom.)
• Consequence: FMO1 NM_001282693.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13
• Publications: 17 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]

ENSG00000231424 (HGNC:40240):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO1	NM_001282693.2	c.-78C>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000617670.6	NP_001269622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO1	ENST00000617670.6	c.-78C>A		5_prime_UTR_variant	Exon 1 of 9	1	NM_001282693.2	ENSP00000481732.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17072 AN: 152130 Hom.: 1150 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.0703

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0820

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.750 AC: 3 AN: 4 Hom.: 1 Cov.: 0 AF XY: 0.750 AC XY: 3 AN XY: 4

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 3 AN: 4

Other (OTH) AC: 0 AN: 0

⚠️ 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 AF: 0.112 AC: 17102 AN: 152248 Hom.: 1153 Cov.: 31 AF XY: 0.116 AC XY: 8609 AN XY: 74436

African (AFR) AF: 0.114 AC: 4748 AN: 41536

American (AMR) AF: 0.185 AC: 2833 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 441 AN: 3472

East Asian (EAS) AF: 0.252 AC: 1297 AN: 5156

South Asian (SAS) AF: 0.234 AC: 1128 AN: 4830

European-Finnish (FIN) AF: 0.0703 AC: 747 AN: 10620

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.0821 AC: 5582 AN: 68018

Other (OTH) AF: 0.113 AC: 240 AN: 2116

Alfa AF: 0.0975 Hom.: 3606

Bravo AF: 0.122

Asia WGS AF: 0.244 AC: 851 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.9
DANN	Benign	0.64
PhyloP100		2.1
PromoterAI		-0.035	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs12720462; hg19: chr1-171217691; COSMIC: COSV105288075;