rs10912675

Positions:

• chr1-171258077-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001282693.2(FMO1):​c.-6-5T>C variant causes a splice region, splice polypyrimidine tract, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_001282693.2 splice_region, splice_polypyrimidine_tract, intron
• 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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• 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/exons	MANE	UniProt
FMO1	NM_001282693.2	c.-6-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000617670.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO1	ENST00000617670.6	c.-6-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001282693.2	P1

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

GnomAD3 exomes AF: 0.310 AC: 77738 AN: 251118 Hom.: 13698 AF XY: 0.306 AC XY: 41496 AN XY: 135722

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 SAS exome AF: 0.344

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

Gnomad4 AMR exome AF: 0.307

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.336

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.299

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

Gnomad4 AMR AF: 0.311

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.371

Alfa AF: 0.322 Hom.: 4177

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

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;