rs1799963

Positions:

• chr11-46739505-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PP5_Strong BP4 BS1_Supporting

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 other,risk factor (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (18 hom., cov: 32)
  • Exomes 𝑓: 0.012 (118 hom.)
• Consequence: F2 NM_000506.5 3_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance; risk factor criteria provided, multiple submitters, no conflicts P:18 U:1 O:6
• Conservation: PhyloP100: 0.878

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP5: Variant 11-46739505-G-A is Pathogenic according to our data. Variant chr11-46739505-G-A is described in ClinVar as [other, 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: {Pathogenic_low_penetrance=1, Likely_pathogenic=1, risk_factor=2, not_provided=1, Uncertain_significance=1, Pathogenic=13}. 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/exons	MANE	Protein	UniProt
F2	NM_000506.5	c.*97G>A		3_prime_UTR_variant	14/14	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.*97G>A		3_prime_UTR_variant	14/14	1	NM_000506.5	ENSP00000308541	P1
F2	ENST00000530231.5			downstream_gene_variant		5		ENSP00000433907

Frequencies

GnomAD3 genomes AF: 0.00957 AC: 1456 AN: 152186 Hom.: 18 Cov.: 32

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

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

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

Submissions summary: Pathogenic:18 Uncertain:1 Other:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombophilia due to thrombin defect Pathogenic:8 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 17, 2009	- -
not provided, no classification provided	literature only	GeneReviews	-	assoc with increased plasma levels of prothrombin -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 02, 2022	ACMG classification criteria: PS4 strong, PP1 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	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 0.0096 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 submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 22, 2020	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 10, 2015	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	F2: PS3:Very Strong, PP1:Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 28, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	Aug 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Nov 10, 2022	- -

Congenital prothrombin deficiency Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Department 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jul 20, 2024	- -
Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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). -
risk factor, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -

Pregnancy loss, recurrent, susceptibility to, 2 Uncertain:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Jun 17, 2009	- -
Uncertain significance, flagged submission	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jun 21, 2019	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

Established risk allele, no assertion criteria provided

research

Department 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 submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 04, 2019

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

risk factor, no assertion criteria provided

literature only

OMIM

Jun 17, 2009

- -

Cerebral palsy Other:1

risk factor, criteria provided, single submitter

research

Neurogenetics Research Program, University of Adelaide

Jun 10, 2021

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

Other links and lift over

dbSNP: rs1799963; hg19: chr11-46761055;