rs3917643

Positions:

• chr1-94536311-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000334047.12(F3):​c.213-147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 711,428 control chromosomes in the GnomAD database, including 849 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 0.038 (176 hom., cov: 32)
  • Exomes 𝑓: 0.043 (673 hom.)
• Consequence: F3 ENST00000334047.12 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.523

Genes affected

F3 (HGNC:3541): (coagulation factor III, tissue factor) This gene encodes coagulation factor III which is a cell surface glycoprotein. This factor enables cells to initiate the blood coagulation cascades, and it functions as the high-affinity receptor for the coagulation factor VII. The resulting complex provides a catalytic event that is responsible for initiation of the coagulation protease cascades by specific limited proteolysis. Unlike the other cofactors of these protease cascades, which circulate as nonfunctional precursors, this factor is a potent initiator that is fully functional when expressed on cell surfaces, for example, on monocytes. There are 3 distinct domains of this factor: extracellular, transmembrane, and cytoplasmic. Platelets and monocytes have been shown to express this coagulation factor under procoagulatory and proinflammatory stimuli, and a major role in HIV-associated coagulopathy has been described. Platelet-dependent monocyte expression of coagulation factor III has been described to be associated with Coronavirus Disease 2019 (COVID-19) severity and mortality. This protein is the only one in the coagulation pathway for which a congenital deficiency has not been described. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F3	NM_001993.5	c.213-147A>G		intron_variant		ENST00000334047.12	NP_001984.1
F3	NM_001178096.2	c.213-147A>G		intron_variant			NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12	c.213-147A>G		intron_variant		1	NM_001993.5	ENSP00000334145	P1
F3	ENST00000370207.4	c.213-147A>G		intron_variant		1		ENSP00000359226
F3	ENST00000480356.1	n.831-147A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 5782 AN: 152080 Hom.: 176 Cov.: 32

Gnomad AFR AF: 0.00922

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.0344

GnomAD4 exome AF: 0.0430 AC: 24037 AN: 559230 Hom.: 673 AF XY: 0.0418 AC XY: 12280 AN XY: 293918

Gnomad4 AFR exome AF: 0.00769

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.0000307

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.0771

Gnomad4 NFE exome AF: 0.0521

Gnomad4 OTH exome AF: 0.0393

GnomAD4 genome AF: 0.0380 AC: 5781 AN: 152198 Hom.: 176 Cov.: 32 AF XY: 0.0384 AC XY: 2858 AN XY: 74416

Gnomad4 AFR AF: 0.00920

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0836

Gnomad4 NFE AF: 0.0563

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0479 Hom.: 29

Bravo AF: 0.0331

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.67

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: rs3917643; hg19: chr1-95001867;