Genetic Variant F3:c.213-147A>G (chr1-94536311-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001993.5(F3):c.213-147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 711,428 control chromosomes in the GnomAD database, including 849 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 0.038 ( 176 hom., cov: 32)

Exomes 𝑓: 0.043 ( 673 hom. )

Consequence

F3
NM_001993.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.523

Publications

17 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F3	NM_001993.5 link	c.213-147A>G		intron_variant	Intron 2 of 5	ENST00000334047.12	NP_001984.1
F3	NM_001178096.2 link	c.213-147A>G		intron_variant	Intron 2 of 4		NP_001171567.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
F3	ENST00000334047.12 link	c.213-147A>G	intron_variant	Intron 2 of 5	1	NM_001993.5	ENSP00000334145.7
F3	ENST00000370207.4 link	c.213-147A>G	intron_variant	Intron 2 of 4	1		ENSP00000359226.4
F3	ENST00000480356.1 link	n.831-147A>G	intron_variant	Intron 3 of 4	5
F3	ENST00000478217.5 link	n.-147A>G	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0380

AC:

5782

AN:

152080

Hom.:

176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00922

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0836

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0563

Gnomad OTH

AF:

0.0344

GnomAD4 exome

AF:

0.0430

AC:

24037

AN:

559230

Hom.:

673

AF XY:

0.0418

AC XY:

12280

AN XY:

293918

show subpopulations

African (AFR)

AF:

0.00769

AC:

115

AN:

14956

American (AMR)

AF:

0.0247

AC:

595

AN:

24088

Ashkenazi Jewish (ASJ)

AF:

0.0227

AC:

349

AN:

15352

East Asian (EAS)

AF:

0.0000307

AC:

AN:

32602

South Asian (SAS)

AF:

0.0146

AC:

752

AN:

51512

European-Finnish (FIN)

AF:

0.0771

AC:

2437

AN:

31628

Middle Eastern (MID)

AF:

0.00636

AC:

AN:

2202

European-Non Finnish (NFE)

AF:

0.0521

AC:

18601

AN:

357034

Other (OTH)

AF:

0.0393

AC:

1173

AN:

29856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1128

2255

3383

4510

5638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0380

AC:

5781

AN:

152198

Hom.:

176

Cov.:

AF XY:

0.0384

AC XY:

2858

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00920

AC:

382

AN:

41536

American (AMR)

AF:

0.0297

AC:

454

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0836

AC:

885

AN:

10580

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0563

AC:

3829

AN:

68000

Other (OTH)

AF:

0.0341

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

286

572

857

1143

1429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0457

Hom.:

315

Bravo

AF:

0.0331

Asia WGS

AF:

0.00751

AC:

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

2.6

(source)

DANN

Benign

0.67

PhyloP100

0.52

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over