NM_000506.5:c.1726-59G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000506.5(F2):c.1726-59G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,613,514 control chromosomes in the GnomAD database, including 197,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 13994 hom., cov: 31)

Exomes 𝑓: 0.49 ( 183774 hom. )

Consequence

F2
NM_000506.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.871

Publications

69 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 11-46739206-G-A is Benign according to our data. Variant chr11-46739206-G-A is described in ClinVar as Benign. ClinVar VariationId is 143996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5 link	c.1726-59G>A		intron_variant	Intron 13 of 13	ENST00000311907.10	NP_000497.1	P00734

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10 link	c.1726-59G>A		intron_variant	Intron 13 of 13	1	NM_000506.5	ENSP00000308541.5		P00734
F2	ENST00000530231.5 link	c.1609-59G>A		intron_variant	Intron 13 of 13	5		ENSP00000433907.1		E9PIT3

Frequencies

GnomAD3 genomes

AF:

0.384

AC:

58279

AN:

151840

Hom.:

13989

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0980

Gnomad AMI

AF:

0.567

Gnomad AMR

AF:

0.444

Gnomad ASJ

AF:

0.521

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.364

Gnomad FIN

AF:

0.548

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.525

Gnomad OTH

AF:

0.424

GnomAD4 exome

AF:

0.491

AC:

718264

AN:

1461554

Hom.:

183774

Cov.:

AF XY:

0.490

AC XY:

355996

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.0809

AC:

2707

AN:

33478

American (AMR)

AF:

0.406

AC:

18136

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.521

AC:

13621

AN:

26128

East Asian (EAS)

AF:

0.150

AC:

5962

AN:

39698

South Asian (SAS)

AF:

0.367

AC:

31673

AN:

86250

European-Finnish (FIN)

AF:

0.554

AC:

29607

AN:

53414

Middle Eastern (MID)

AF:

0.450

AC:

2592

AN:

5766

European-Non Finnish (NFE)

AF:

0.527

AC:

585497

AN:

1111712

Other (OTH)

AF:

0.471

AC:

28469

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

21877

43754

65631

87508

109385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16322

32644

48966

65288

81610

<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:

0.384

AC:

58281

AN:

151960

Hom.:

13994

Cov.:

AF XY:

0.383

AC XY:

28462

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.0976

AC:

4050

AN:

41486

American (AMR)

AF:

0.443

AC:

6755

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.521

AC:

1810

AN:

3472

East Asian (EAS)

AF:

0.173

AC:

894

AN:

5160

South Asian (SAS)

AF:

0.364

AC:

1755

AN:

4818

European-Finnish (FIN)

AF:

0.548

AC:

5784

AN:

10552

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.525

AC:

35679

AN:

67914

Other (OTH)

AF:

0.429

AC:

905

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1584

3168

4751

6335

7919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.457

Hom.:

31333

Bravo

AF:

0.365

Asia WGS

AF:

0.285

AC:

996

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11434686, 14504098, 16981886, 19652888, 17059428) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital prothrombin deficiency;C0948008:Ischemic stroke;C3160733:Thrombophilia due to thrombin defect;C3280672:Pregnancy loss, recurrent, susceptibility to, 2

Benign:1

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thrombophilia due to thrombin defect

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.6

(source)

DANN

Benign

0.75

PhyloP100

0.87

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over