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rs1799963

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5BP4BS1_SupportingBS2

The NM_000506.5(F2):c.*97G>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 0.0114 in 1,480,018 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars).

Frequency

Genomes: 𝑓 0.0096 ( 18 hom., cov: 32)
Exomes 𝑓: 0.012 ( 118 hom. )

Consequence

F2
NM_000506.5 3_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:14U:2O: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP5
Variant 11-46739505-G-A is Pathogenic according to our data. Variant chr11-46739505-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity, risk_factor]. Clinvar id is 13310.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=10, risk_factor=2, Pathogenic_low_penetrance=1, Uncertain_significance=2, 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. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd at 18 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
F2NM_000506.5 linkuse as main transcriptc.*97G>A 3_prime_UTR_variant 14/14 ENST00000311907.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
F2ENST00000311907.10 linkuse as main transcriptc.*97G>A 3_prime_UTR_variant 14/141 NM_000506.5 P1
F2ENST00000530231.5 linkuse as main transcript downstream_gene_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00957
AC:
1456
AN:
152186
Hom.:
18
Cov.:
32
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.:
19
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.:
18
Cov.:
32
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.:
2
Bravo
AF:
0.0105
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor
Submissions summary: Pathogenic:14Uncertain:2Other:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Thrombophilia due to thrombin defect Pathogenic:8Other:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 14, 2023Variant 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 0.0096 in 150958 control chromosomes in the gnomAD database (v3.1 genomes dataset), including 18 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 (e.g. Kujovich_2006, Ho_2006, Foy_2009, Gonzalez_2016, Shemes_2017, Baylis_2021), describing this variant as the second most common inherited thrombophilic risk factor. In addition, a recent study reported an even higher relative risk for venous thromboembolism (OR = 5 (95% CI 2.1-11.92)) for homozygous individuals (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. 12 submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=5), VUS (n=2), benign (n=1), or risk factor (n=4). Based on the evidence outlined above, the variant represents a well-known hypermorphic mutation, 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. -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinAug 02, 2022ACMG classification criteria: PS4 strong, PP1 strong -
Pathogenic, criteria provided, single submitterclinical testingISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology-- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 22, 20200101 - 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 -
Pathogenic, criteria provided, single submitterclinical testingCounsylAug 10, 2015- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 17, 2009- -
not provided, no classification providedliterature onlyGeneReviews-assoc with increased plasma levels of prothrombin -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 27, 2023- -
Congenital prothrombin deficiency Pathogenic:2Uncertain:1Other:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
risk factor, no assertion criteria providedcurationReproductive Health Research and Development, BGI GenomicsJan 06, 2020NM_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. -
Pathogenic, low penetrance, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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). -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 13, 2022Also 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) -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 28, 2022The 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. -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024F2: PS3:Very Strong, PP1:Strong -
Pregnancy loss, recurrent, susceptibility to, 2 Uncertain:1Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJun 17, 2009- -
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJun 21, 2019This 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
Established risk allele, no assertion criteria providedresearchDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Venous thromboembolism Other:1
risk factor, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 04, 2019F2 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
risk factor, no assertion criteria providedliterature onlyOMIMJun 17, 2009- -
Cerebral palsy Other:1
risk factor, criteria provided, single submitterresearchNeurogenetics Research Program, University of AdelaideJun 10, 2021Heterozygosity 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.

Other links and lift over

dbSNP: rs1799963; hg19: chr11-46761055; API