rs1799963

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting

The NM_000506.5(F2):c.*97G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,480,018 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic low penetrance,risk factor (★★).

Frequency

Genomes: 𝑓 0.0096 ( 18 hom., cov: 32)

Exomes 𝑓: 0.012 ( 118 hom. )

Consequence

F2
NM_000506.5 splice_region

Scores

Clinical Significance

Pathogenic/Likely pathogenic/Pathogenic, low penetrance; risk factor criteria provided, multiple submitters, no conflicts P:20U:1O:6

Conservation

PhyloP100: 0.878

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PP5

Variant 11-46739505-G-A is Pathogenic according to our data. Variant chr11-46739505-G-A is described in ClinVar as [Pathogenic_low_penetrance, risk_factor]. Clinvar id is 13310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, risk_factor=2, Pathogenic_low_penetrance=1, Uncertain_significance=1, Pathogenic=15, not_provided=1}. Variant chr11-46739505-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00957 (1457/152304) while in subpopulation AMR AF= 0.0151 (231/15296). AF 95% confidence interval is 0.0135. There are 18 homozygotes in gnomad4. There are 666 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5 link	c.*97G>A		splice_region_variant	Exon 14 of 14	ENST00000311907.10	NP_000497.1	P00734
F2	NM_000506.5 link	c.*97G>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000311907.10	NP_000497.1	P00734

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
F2	ENST00000311907.10 link	c.*97G>A	splice_region_variant	Exon 14 of 14	1	NM_000506.5	ENSP00000308541.5	P00734
F2	ENST00000311907.10 link	c.*97G>A	3_prime_UTR_variant	Exon 14 of 14	1	NM_000506.5	ENSP00000308541.5	P00734
F2	ENST00000530231.5 link	c.*97G>A	downstream_gene_variant		5		ENSP00000433907.1	E9PIT3

Frequencies

GnomAD3 genomes

AF:

0.00957

AC:

1456

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0136

Gnomad OTH

AF:

0.0163

GnomAD4 exome

AF:

0.0116

AC:

15393

AN:

1327714

Hom.:

118

Cov.:

AF XY:

0.0114

AC XY:

7614

AN XY:

666466

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.0102

Gnomad4 ASJ exome

AF:

0.0358

Gnomad4 EAS exome

AF:

0.0000513

Gnomad4 SAS exome

AF:

0.00203

Gnomad4 FIN exome

AF:

0.00488

Gnomad4 NFE exome

AF:

0.0129

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.00957

AC:

1457

AN:

152304

Hom.:

Cov.:

AF XY:

0.00894

AC XY:

666

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.0151

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00518

Gnomad4 NFE

AF:

0.0136

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.0105

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance; risk factor

Submissions summary: Pathogenic:20Uncertain:1Other:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thrombophilia due to thrombin defect

Pathogenic:9Other:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4,PM2 -

Oct 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: F2 c.*97G>A (also known as c.20210G>A or G20210A) is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.011 in 1474868 control chromosomes in the gnomAD database (v.4.1 dataset), including 134 homozygotes. Heterozygosity for this variant is associated with increased prothrombin levels (e.g. Gehring_2001, Foy_2009), and several meta-analyses reported 2- to 4-fold increased risk of venous thrombosis, describing this variant as the second most common inherited thrombophilic risk factor (e.g. Kujovich_2006, Ho_2006, Foy_2009, Gonzalez_2016, Shemes_2017, Baylis_2021, Ryu_2024). In addition, homozygous individuals were reported to have an even higher relative risk (OR = 5 (95% CI 2.1-11.92)) for venous thromboembolism (Shemes_2017). At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated that the variant caused increased cleavage site recognition and subsequently increased 3' end processing, mRNA accumulation, and increased protein synthesis (Gehring_2001), which can explain the elevated prothrombin plasma concentrations. The following publications have been ascertained in the context of this evaluation (PMID: 34110897, 19289024, 11443298, 27031503, 16606808, 20301327, 28707429, 38498041). ClinVar contains an entry for this variant (Variation ID: 13310). Based on the evidence outlined above, the variant represents a well-known hypermorphic polymorphism, which causes an increase in normal gene function resulting in an increased risk of thrombophilia, therefore it was classified as a 'low penetrance pathogenic' (i.e. risk) variant. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

assoc with increased plasma levels of prothrombin -

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2015

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 17, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 02, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PP1 strong -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with thrombophilia due to a thrombin defect (MIM#188050) (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. However, this variant is described to be semi-dominant as both homozygotes and heterozygotes are at increased risk for venous thromboembolism, with homozygotes having a greater risk (OMIM, PMID: 30297698). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30297698). (I) 0217 - Non-coding variant with known effect. The c.*97G>A results in gain-of-function with elevated protein synthesis (PMID: 11443298). (SP) 0251 - This variant is heterozygous. (I) 0303 - Variant is present in gnomAD (v3) >=0.01 for a dominant condition (1343 heterozygotes, 17 homozygotes). (SB) 0504 - Same nucleotide change has been observed in placental mammals. (SB) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic for venous thromboembolism and as a risk factor for both stroke and recurrent pregnancy loss (ClinVar; PMID: 30297698). A review study showed this variant is more prevalent in affected Italian, Brazilian and German individuals (PMID: 27031503). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:6

Sep 28, 2022

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F2 c.*97G>A variant, previously known as prothrombin 20210G>A or G20210A, occurs in the 3' untranslated region of the F2 gene and results in the substitution of a guanine at nucleotide position c.*97 with an adenine. The c.*97G>A variant is a well-documented variant associated with an increased risk of venous thromboembolism (VTE). Across a selection of the available literature, heterozygosity for the c.*97G>A variant has been estimated to confer an increased risk of VTE between 1.9 to 11.5 fold, with the majority of estimates falling between 2 and 5 fold. Homozygosity for this variant is presumed to confer a higher risk of VTE, however the magnitude of this risk is not well defined (PMID: 20301327; PMID: 30297698). Data from a 2009 meta-analysis indicated that while heterozygosity for the c.*97G>A variant confers an increased risk for initial VTE, it was not predictive of recurrent events (PMID: 19531787). The highest frequency of this allele in the Genome Aggregation Database is 0.03165 in the Middle Eastern population (version 3.1.2). This frequency is high but is consistent with disease prevalence estimates and incomplete penetrance among variant carriers. Functional studies indicate that the c.*97G>A variant enhances 3' end processing of pre-mRNA, which results in increased mRNA production and elevated prothrombin levels (PMID: 8916933; PMID: 15059842). Based on the collective evidence, the c.*97G>A variant is classified as pathogenic with reduced penetrance for thrombophilia due to thrombin defect. -

Aug 23, 2024

Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

F2: PS3:Very Strong, PP1:Strong -

Nov 10, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as 20210G>A and G20210A due to alternate nomenclature; Published functional studies demonstrate elevated plasma levels of prothrombin (Danckwardt et al., 2004); This variant is associated with the following publications: (PMID: 22909823, 26732783, 29431110, 25528068, 26422681, 25772935, 15059842, 22021457, 19356951, 22023246, 20723024, 24619398, 11583312, 8916933, 25977387, 22141575, 27031503, 19652888, 15726653, 28707429, 22023244, 31472339, 25028703, 32155011, 26148378, 24016568, 25693916, 29974397, 30005273, 26226452, 34570182, 16411414, 9238178, 11684865, 10456622, 25509247, 11864707, 10507841, 33258288, 11737249, 11064483, 10406905, 11190909, 11114826) -

Congenital prothrombin deficiency

Pathogenic:3Other:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic, low penetrance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the F2 gene. It does not change the encoded amino acid sequence of the F2 protein. This variant is present in population databases (rs1799963, gnomAD 1.8%), and has an allele count higher than expected for a pathogenic variant. This sequence change (rs1799963) is a common variant associated with prothrombin-related thrombophilia. It has historically been called prothrombin 20210G>A. As many as 1.7% to 3% of the general U.S. and European populations are heterozygous for this sequence change (PMID: 9569177, 20301327). Heterozygosity for this variant is associated with increased prothrombin levels, and a 2- to 4-fold increased risk of venous thrombosis over the baseline population (PMID: 19289024, 20301327). ClinVar contains an entry for this variant (Variation ID: 13310). For these reasons, this variant has been classified as Pathogenic (low penetrance). -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: curation

NM_000506.3:c.*97G>A was reported as 20210G>A in previous publications. NM_000506.3:c.*97G>A in the F2 gene has an allele frequency of 0.012 in European (non-Finnish) subpopulation in the gnomAD database. This variant is a common variant associated with prothrombin-related thrombophilia (PMID: 9569177, 20301327). Heterozygosity for this variant is associated with increased prothrombin levels, and a 2- to 4-fold increased risk of venous thrombosis over the baseline population (PMID: 19289024). Rosendaal et al. (1997) found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (PMID: 9569177). For these reasons, this variant has been classified as At-risk. Taken together, we interprete this variant as a risk factor. -

Jul 20, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The F2 3' UTR c.*97G>A variant was identified in dbSNP (rs1799963) and Clinvar (classified as pathogenic by Counsyl and Mendelics in relation to venous thrombosis; mixed predictions of pathogenicity in association with congenital prothrombin deficiency). The F2 3' UTR c.*97G>A variant, historically called the prothrombin 20210G>A variant, is associated with increased prothrombin levels in the heterozygous state and has been found to be associated with a 2- to 3-fold increased risk of venous thrombosis over the baseline population (Foy_2009_19289024; Ho_2006_16606808). However, the estimated population attributable risk of recurrence for venous thromboembolism is modest (approximately 6.7%; 5% CI, 3.4-9.9%) and likely does not warrant extended anticoagulation treatment (Ho_2006_16606808). The prothrombin 20210G>A variant disrupts the F2 cleavage signal within the 3' UTR, causing increased cleavage site recognition and subsequently increased 3' end processing, mRNA accumulation, protein synthesis, and ultimately elevated plasma prothrombin concentrations (Gehring_2001_11443298). The variant was identified in control databases in 265 of 31396 chromosomes (1 homozygous) at a frequency of 0.8441%, and was observed at the highest frequency in the Latino population in 15 of 848 chromosomes (freq: 0.01769) (Genome Aggregation Database March 6, 2019, v2.1.1). The The F2 3' UTR c.*97G>A variant is not conserved in mammals. In silico predictions predicting the impact of the The F2 3' UTR c.*97G>A variant to the protein are not available. In summary, based on the above information this variant meets our laboratory's criteria to be classified as pathogenic. -

Pregnancy loss, recurrent, susceptibility to, 2

Uncertain:1Other:1

Jun 17, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 21, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS1. -

Thrombophilia caused by F2 prothrombin deficiency

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Established risk allele

Review Status: no assertion criteria provided

Collection Method: research

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

Pathogenic:1

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Venous thromboembolism

Other:1

Dec 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: clinical testing

F2 c.*97G>A (also known as c.20210G>A or G20210A) has been associated with increased risk for venous thromboembolism. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Latino ancestry (1.8%, Genome Aggregation Database (gnomAD); rs121909293) and is present in ClinVar (ID: 13310). At least two large meta analyses has reported an odds ratio of 3.18-5.18 for developing venous thromboembolism (OR=3.18 [95% CI 2.19-3.46] Gohil 2009, OR=5.38 [95% CI 3.96-8.58] Gonzalez 2016). In vitro functional studies provide some evidence that the c.*97G>A variant may impact protein function (Gehring 2001, Danckwardt 2004). In summary, this variant is not expected to cause highly penetrant Mendelian disease. c.*97G>A variant is an established risk factor for venous thromboembolism. -

Ischemic stroke

Other:1

Jun 17, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cerebral palsy

Other:1

Jun 10, 2021

Neurogenetics Research Program, University of Adelaide

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: research

Heterozygosity for F2 c.*97G>A (G20210A, rs1799963) is the second most common genetic risk factor for venous thrombosis -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.1

DANN

Benign

0.76

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over