Genetic Variant F3:c.*197G>A (chr1-94530263-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0310

Variant links:

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]

F3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 link	c.*197G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000334047.12	NP_001984.1	P13726-1
F3	NM_001178096.2 link	c.*208G>A		3_prime_UTR_variant	Exon 5 of 5		NP_001171567.1	P13726-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F3	ENST00000334047 link	c.*197G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_001993.5	ENSP00000334145.7		P13726-1
F3	ENST00000370207 link	c.*208G>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000359226.4		P13726-2

Frequencies

GnomAD3 genomes

AF:

0.287

AC:

43537

AN:

151750

Hom.:

6488

Cov.:

show subpopulations

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.:

AF XY:

0.302

AC XY:

67051

AN XY:

221892

show subpopulations

Gnomad4 AFR exome

AF:

0.256

Gnomad4 AMR exome

AF:

0.233

Gnomad4 ASJ exome

AF:

0.309

Gnomad4 EAS exome

AF:

0.454

Gnomad4 SAS exome

AF:

0.434

Gnomad4 FIN exome

AF:

0.395

Gnomad4 NFE exome

AF:

0.264

Gnomad4 OTH exome

AF:

0.295

GnomAD4 genome

AF:

0.287

AC:

43534

AN:

151868

Hom.:

6481

Cov.:

AF XY:

0.296

AC XY:

21948

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.257

Gnomad4 AMR

AF:

0.250

Gnomad4 ASJ

AF:

0.321

Gnomad4 EAS

AF:

0.473

Gnomad4 SAS

AF:

0.472

Gnomad4 FIN

AF:

0.399

Gnomad4 NFE

AF:

0.268

Gnomad4 OTH

AF:

0.252

Alfa

AF:

0.263

Hom.:

1695

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over