rs10912675

Variant names:

• chr1-171258077-T-C
• rs10912675
• ENST00000354841:c.-11T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PVS1_Supporting BP6 BA1

The NM_001282692.1(FMO1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,613,342 control chromosomes in the GnomAD database, including 77,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.39 (14559 hom., cov: 32)
  • Exomes 𝑓: 0.28 (63102 hom.)
• Consequence: FMO1 NM_001282692.1 start_lost
• Scores: Splicing: ADA: 0.0001335
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45

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

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 5 codons. Genomic position: 171258088. Lost 0.008 part of the original CDS.
• BP6: Variant 1-171258077-T-C is Benign according to our data. Variant chr1-171258077-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMO1	NM_001282693.2	c.-6-5T>C		splice_region_variant, intron_variant	Intron 1 of 8	ENST00000617670.6	NP_001269622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMO1	ENST00000617670.6	c.-6-5T>C		splice_region_variant, intron_variant	Intron 1 of 8	1	NM_001282693.2	ENSP00000481732.1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59893 AN: 151948 Hom.: 14510 Cov.: 32

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.310 AC: 77738 AN: 251118 AF XY: 0.306

Gnomad AFR exome AF: 0.711

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.190

Gnomad FIN exome AF: 0.273

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.281

GnomAD4 exome AF: 0.284 AC: 414494 AN: 1461276 Hom.: 63102 Cov.: 33 AF XY: 0.284 AC XY: 206651 AN XY: 726936

Gnomad4 AFR exome AF: 0.714 AC: 23912 AN: 33468

Gnomad4 AMR exome AF: 0.307 AC: 13706 AN: 44710

Gnomad4 ASJ exome AF: 0.285 AC: 7458 AN: 26132

Gnomad4 EAS exome AF: 0.206 AC: 8188 AN: 39682

Gnomad4 SAS exome AF: 0.336 AC: 28968 AN: 86242

Gnomad4 FIN exome AF: 0.273 AC: 14572 AN: 53364

Gnomad4 NFE exome AF: 0.268 AC: 297934 AN: 1111570

Gnomad4 Remaining exome AF: 0.299 AC: 18054 AN: 60370

GnomAD4 genome AF: 0.395 AC: 59993 AN: 152066 Hom.: 14559 Cov.: 32 AF XY: 0.391 AC XY: 29100 AN XY: 74336

Gnomad4 AFR AF: 0.698 AC: 0.698408 AN: 0.698408

Gnomad4 AMR AF: 0.311 AC: 0.311191 AN: 0.311191

Gnomad4 ASJ AF: 0.294 AC: 0.29371 AN: 0.29371

Gnomad4 EAS AF: 0.201 AC: 0.2014 AN: 0.2014

Gnomad4 SAS AF: 0.351 AC: 0.351391 AN: 0.351391

Gnomad4 FIN AF: 0.278 AC: 0.277505 AN: 0.277505

Gnomad4 NFE AF: 0.273 AC: 0.273305 AN: 0.273305

Gnomad4 OTH AF: 0.371 AC: 0.370739 AN: 0.370739

Alfa AF: 0.326 Hom.: 19358

Bravo AF: 0.408

Asia WGS AF: 0.309 AC: 1077 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.65
DANN	Benign	0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs10912675; hg19: chr1-171227216; COSMIC: COSV61448222; COSMIC: COSV61448222;