rs610277

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001993.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F3	NM_001993.5	MANE Select	c.591+87T>C		intron	N/A	NP_001984.1	P13726-1
	F3	NM_001178096.2		c.591+87T>C		intron	N/A	NP_001171567.1	P13726-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F3	ENST00000334047.12	TSL:1 MANE Select	c.591+87T>C		intron	N/A	ENSP00000334145.7	P13726-1
	F3	ENST00000370207.4	TSL:1	c.591+87T>C		intron	N/A	ENSP00000359226.4	P13726-2
	F3	ENST00000949532.1		c.591+87T>C		intron	N/A	ENSP00000619591.1

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

African (AFR) AF: 0.00568 AC: 152 AN: 26754

American (AMR) AF: 0.0361 AC: 1198 AN: 33172

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 1428 AN: 22050

East Asian (EAS) AF: 0.141 AC: 5041 AN: 35718

South Asian (SAS) AF: 0.0436 AC: 3043 AN: 69774

European-Finnish (FIN) AF: 0.0344 AC: 1632 AN: 47414

Middle Eastern (MID) AF: 0.0450 AC: 211 AN: 4686

European-Non Finnish (NFE) AF: 0.0376 AC: 34436 AN: 915714

Other (OTH) AF: 0.0400 AC: 2049 AN: 51280

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

African (AFR) AF: 0.00618 AC: 257 AN: 41574

American (AMR) AF: 0.0327 AC: 500 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 234 AN: 3468

East Asian (EAS) AF: 0.122 AC: 628 AN: 5162

South Asian (SAS) AF: 0.0402 AC: 194 AN: 4820

European-Finnish (FIN) AF: 0.0366 AC: 388 AN: 10610

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0347 AC: 2360 AN: 68022

Other (OTH) AF: 0.0274 AC: 58 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.051
DANN	Benign	0.55
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs610277; hg19: chr1-94998559;