rs696619

Variant names:

• chr1-94539664-G-A
• rs696619
• NM_001993.5:c.212+593C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001993.5(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 NM_001993.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
F3	NM_001993.5	c.212+593C>T		intron_variant	Intron 2 of 5	ENST00000334047.12	NP_001984.1
F3	NM_001178096.2	c.212+593C>T		intron_variant	Intron 2 of 4		NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12	c.212+593C>T		intron_variant	Intron 2 of 5	1	NM_001993.5	ENSP00000334145.7
F3	ENST00000370207.4	c.212+593C>T		intron_variant	Intron 2 of 4	1		ENSP00000359226.4
F3	ENST00000480356.1	n.830+593C>T		intron_variant	Intron 3 of 4	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

African (AFR) AF: 0.164 AC: 6813 AN: 41488

American (AMR) AF: 0.440 AC: 6720 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1832 AN: 3466

East Asian (EAS) AF: 0.692 AC: 3551 AN: 5128

South Asian (SAS) AF: 0.471 AC: 2257 AN: 4788

European-Finnish (FIN) AF: 0.450 AC: 4748 AN: 10544

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.421 AC: 28593 AN: 67940

Other (OTH) AF: 0.369 AC: 778 AN: 2108

Alfa AF: 0.407 Hom.: 22316

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
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs696619; hg19: chr1-95005220;