rs1324214

Positions:

• chr1-94531732-G-A
• chr1-94531732-G-C

Variant summary

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

The NM_001993.5(F3):​c.751+589C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 152,156 control chromosomes in the GnomAD database, including 3,678 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 0.21 (3678 hom., cov: 33)
• Consequence: F3 NM_001993.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F3	NM_001993.5	c.751+589C>T		intron_variant		ENST00000334047.12	NP_001984.1
F3	NM_001178096.2	c.592-1136C>T		intron_variant			NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12	c.751+589C>T		intron_variant		1	NM_001993.5	ENSP00000334145	P1
F3	ENST00000370207.4	c.592-1136C>T		intron_variant		1		ENSP00000359226

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32543 AN: 152038 Hom.: 3669 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.209

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.214 AC: 32565 AN: 152156 Hom.: 3678 Cov.: 33 AF XY: 0.214 AC XY: 15926 AN XY: 74386

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.208

Alfa AF: 0.235 Hom.: 4186

Bravo AF: 0.214

Asia WGS AF: 0.211 AC: 734 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.71

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: rs1324214; hg19: chr1-94997288;