rs5898

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000506.5(F2):c.1233G>A(p.Pro411Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 1,610,160 control chromosomes in the GnomAD database, including 5,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 390 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5258 hom. )

Consequence

F2
NM_000506.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.50

Publications

14 publications found

Variant links:

Genes affected

F2 (HGNC:3535): (coagulation factor II, thrombin) This gene encodes the prothrombin protein (also known as coagulation factor II). This protein is proteolytically cleaved in multiple steps to form the activated serine protease thrombin. The activated thrombin enzyme plays an important role in thrombosis and hemostasis by converting fibrinogen to fibrin during blood clot formation, by stimulating platelet aggregation, and by activating additional coagulation factors. Thrombin also plays a role in cell proliferation, tissue repair, and angiogenesis as well as maintaining vascular integrity during development and postnatal life. Peptides derived from the C-terminus of this protein have antimicrobial activity against E. coli and P. aeruginosa. Mutations in this gene lead to various forms of thrombosis and dysprothrombinemia. Rapid increases in cytokine levels following coronavirus infections can dysregulate the coagulation cascade and produce thrombosis, compromised blood supply, and organ failure. [provided by RefSeq, May 2020]

F2 Gene-Disease associations (from GenCC):

thrombophilia due to thrombin defect
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
congenital prothrombin deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

F2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 11-46728098-G-A is Benign according to our data. Variant chr11-46728098-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.5 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000506.5. 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
	F2	NM_000506.5	MANE Select	c.1233G>A	p.Pro411Pro	synonymous	Exon 10 of 14	NP_000497.1	P00734

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
F2	ENST00000311907.10	TSL:1 MANE Select	c.1233G>A	p.Pro411Pro	synonymous	Exon 10 of 14	ENSP00000308541.5	P00734
F2	ENST00000862106.1		c.1329G>A	p.Pro443Pro	synonymous	Exon 11 of 15	ENSP00000532165.1
F2	ENST00000862118.1		c.1281G>A	p.Pro427Pro	synonymous	Exon 10 of 14	ENSP00000532177.1

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10033

AN:

151882

Hom.:

392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0352

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.0489

Gnomad ASJ

AF:

0.0927

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0644

Gnomad FIN

AF:

0.0732

Gnomad MID

AF:

0.0828

Gnomad NFE

AF:

0.0896

Gnomad OTH

AF:

0.0686

GnomAD2 exomes

AF:

0.0656

AC:

16034

AN:

244568

AF XY:

0.0680

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.0325

Gnomad ASJ exome

AF:

0.0991

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.0714

Gnomad NFE exome

AF:

0.0867

Gnomad OTH exome

AF:

0.0746

GnomAD4 exome

AF:

0.0800

AC:

116640

AN:

1458160

Hom.:

5258

Cov.:

AF XY:

0.0801

AC XY:

58030

AN XY:

724818

show subpopulations

African (AFR)

AF:

0.0292

AC:

977

AN:

33426

American (AMR)

AF:

0.0342

AC:

1514

AN:

44286

Ashkenazi Jewish (ASJ)

AF:

0.0949

AC:

2465

AN:

25962

East Asian (EAS)

AF:

0.000227

AC:

AN:

39676

South Asian (SAS)

AF:

0.0641

AC:

5449

AN:

84998

European-Finnish (FIN)

AF:

0.0759

AC:

4034

AN:

53126

Middle Eastern (MID)

AF:

0.104

AC:

598

AN:

5766

European-Non Finnish (NFE)

AF:

0.0874

AC:

97059

AN:

1110592

Other (OTH)

AF:

0.0752

AC:

4535

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

6147

12294

18441

24588

30735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3480

6960

10440

13920

17400

<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:

0.0660

AC:

10027

AN:

152000

Hom.:

390

Cov.:

AF XY:

0.0652

AC XY:

4841

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.0352

AC:

1458

AN:

41468

American (AMR)

AF:

0.0489

AC:

746

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0927

AC:

322

AN:

3472

East Asian (EAS)

AF:

0.00136

AC:

AN:

5162

South Asian (SAS)

AF:

0.0639

AC:

306

AN:

4792

European-Finnish (FIN)

AF:

0.0732

AC:

774

AN:

10572

Middle Eastern (MID)

AF:

0.0822

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0896

AC:

6091

AN:

67962

Other (OTH)

AF:

0.0669

AC:

141

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

459

917

1376

1834

2293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0783

Hom.:

883

Bravo

AF:

0.0624

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital prothrombin deficiency (2)

not provided (2)

not specified (1)

Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.91

(source)

DANN

Benign

0.71

PhyloP100

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over