1-94530263-C-T

Variant names:

• chr1-94530263-C-T
• rs3354
• NM_001993.5:c.*197G>A

Variant summary

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

The NM_001993.5(F3):​c.*197G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 580,954 control chromosomes in the GnomAD database, including 27,202 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 0.29 (6481 hom., cov: 31)
  • Exomes 𝑓: 0.30 (20721 hom.)
• Consequence: F3 NM_001993.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0310
• Publications: 15 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F3	NM_001993.5	c.*197G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000334047.12	NP_001984.1
F3	NM_001178096.2	c.*208G>A		3_prime_UTR_variant	Exon 5 of 5		NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047.12	c.*197G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_001993.5	ENSP00000334145.7
F3	ENST00000370207.4	c.*208G>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000359226.4

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43537 AN: 151750 Hom.: 6488 Cov.: 31

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.247

GnomAD4 exome AF: 0.299 AC: 128312 AN: 429086 Hom.: 20721 Cov.: 6 AF XY: 0.302 AC XY: 67051 AN XY: 221892

African (AFR) AF: 0.256 AC: 3189 AN: 12460

American (AMR) AF: 0.233 AC: 3863 AN: 16614

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 3816 AN: 12332

East Asian (EAS) AF: 0.454 AC: 13269 AN: 29246

South Asian (SAS) AF: 0.434 AC: 13708 AN: 31566

European-Finnish (FIN) AF: 0.395 AC: 10456 AN: 26450

Middle Eastern (MID) AF: 0.233 AC: 637 AN: 2738

European-Non Finnish (NFE) AF: 0.264 AC: 72154 AN: 273170

Other (OTH) AF: 0.295 AC: 7220 AN: 24510

GnomAD4 genome AF: 0.287 AC: 43534 AN: 151868 Hom.: 6481 Cov.: 31 AF XY: 0.296 AC XY: 21948 AN XY: 74196

African (AFR) AF: 0.257 AC: 10665 AN: 41424

American (AMR) AF: 0.250 AC: 3805 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1112 AN: 3466

East Asian (EAS) AF: 0.473 AC: 2440 AN: 5158

South Asian (SAS) AF: 0.472 AC: 2272 AN: 4810

European-Finnish (FIN) AF: 0.399 AC: 4194 AN: 10520

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18226 AN: 67936

Other (OTH) AF: 0.252 AC: 531 AN: 2108

Alfa AF: 0.264 Hom.: 2082

Bravo AF: 0.269

Asia WGS AF: 0.457 AC: 1586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.3
DANN	Benign	0.63
PhyloP100		0.031
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: rs3354; hg19: chr1-94995819; COSMIC: COSV61844926; COSMIC: COSV61844926;