rs696619

Positions:

• chr1-94539664-G-A
• chr1-94539664-G-C

Variant summary

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

The ENST00000334047.12(F3):​c.212+593C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 151,940 control chromosomes in the GnomAD database, including 11,696 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 0.37 (11696 hom., cov: 32)
• Consequence: F3 ENST00000334047.12 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317

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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F3	NM_001993.5	c.212+593C>T		intron_variant		ENST00000334047.12	NP_001984.1
F3	NM_001178096.2	c.212+593C>T		intron_variant			NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12	c.212+593C>T		intron_variant		1	NM_001993.5	ENSP00000334145	P1
F3	ENST00000370207.4	c.212+593C>T		intron_variant		1		ENSP00000359226
F3	ENST00000480356.1	n.830+593C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55544 AN: 151822 Hom.: 11692 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.367

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

GnomAD4 genome AF: 0.366 AC: 55556 AN: 151940 Hom.: 11696 Cov.: 32 AF XY: 0.373 AC XY: 27719 AN XY: 74234

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.529

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.471

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.369

Alfa AF: 0.416 Hom.: 18213

Bravo AF: 0.353

Asia WGS AF: 0.541 AC: 1879 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.45

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: rs696619; hg19: chr1-95005220;