rs610277

Variant names:

• chr1-94533003-A-G
• rs610277
• NM_001993.5:c.591+87T>C

Variant summary

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

The NM_001993.5(F3):​c.591+87T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,358,838 control chromosomes in the GnomAD database, including 1,439 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 0.031 (118 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1321 hom.)
• Consequence: F3 NM_001993.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55

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 (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F3	NM_001993.5	c.591+87T>C		intron_variant	Intron 4 of 5	ENST00000334047.12	NP_001984.1
F3	NM_001178096.2	c.591+87T>C		intron_variant	Intron 4 of 4		NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12	c.591+87T>C		intron_variant	Intron 4 of 5	1	NM_001993.5	ENSP00000334145.7
F3	ENST00000370207.4	c.591+87T>C		intron_variant	Intron 4 of 4	1		ENSP00000359226.4
F3	ENST00000478217.5	n.466T>C		non_coding_transcript_exon_variant	Exon 2 of 2	3
F3	ENST00000480356.1	n.*103T>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4640 AN: 152158 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0675

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0400

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0258

GnomAD4 exome AF: 0.0408 AC: 49190 AN: 1206562 Hom.: 1321 Cov.: 16 AF XY: 0.0411 AC XY: 24813 AN XY: 604426

Gnomad4 AFR exome AF: 0.00568

Gnomad4 AMR exome AF: 0.0361

Gnomad4 ASJ exome AF: 0.0648

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.0436

Gnomad4 FIN exome AF: 0.0344

Gnomad4 NFE exome AF: 0.0376

Gnomad4 OTH exome AF: 0.0400

GnomAD4 genome AF: 0.0305 AC: 4646 AN: 152276 Hom.: 118 Cov.: 32 AF XY: 0.0319 AC XY: 2376 AN XY: 74462

Gnomad4 AFR AF: 0.00618

Gnomad4 AMR AF: 0.0327

Gnomad4 ASJ AF: 0.0675

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.0402

Gnomad4 FIN AF: 0.0366

Gnomad4 NFE AF: 0.0347

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0324 Hom.: 26

Bravo AF: 0.0293

Asia WGS AF: 0.0570 AC: 197 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	0.051
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs610277; hg19: chr1-94998559;