rs1799963

Variant names:

• chr11-46739505-G-A
• rs1799963
• NM_000506.5:c.*97G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 12P and 6B. PS3 PP5_Very_Strong BP4 BS1_Supporting BS2

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 (★★). ClinVar reports functional evidence for this variant: "SCV001552413: 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)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0096 (18 hom., cov: 32)
  • Exomes 𝑓: 0.012 (118 hom.)
• Consequence: F2 NM_000506.5 splice_region
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance; risk factor criteria provided, multiple submitters, no conflicts P:23 U:1 O:6
• Conservation: PhyloP100: 0.878
• Publications: 3519 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001552413: 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).; SCV001262797: 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).; SCV001822471: Published functional studies demonstrate elevated plasma levels of prothrombin (Danckwardt et al., 2004); SCV003844696: "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." PMID: 34110897; SCV003921890: The c.*97G>A variant results in gain-of-function with elevated protein synthesis (PMID: 11443298); SCV006583511: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID:15059842, 8916933
• PP5: Variant 11-46739505-G-A is Pathogenic according to our data. Variant chr11-46739505-G-A is described in ClinVar as Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance|risk_factor. ClinVar VariationId is 13310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

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.*97G>A		splice_region	Exon 14 of 14	NP_000497.1	P00734
	F2	NM_000506.5	MANE Select	c.*97G>A		3_prime_UTR	Exon 14 of 14	NP_000497.1	P00734

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	ENST00000311907.10	TSL:1 MANE Select	c.*97G>A		splice_region	Exon 14 of 14	ENSP00000308541.5	P00734
	F2	ENST00000311907.10	TSL:1 MANE Select	c.*97G>A		3_prime_UTR	Exon 14 of 14	ENSP00000308541.5	P00734
	F2	ENST00000862118.1		c.*97G>A		splice_region	Exon 14 of 14	ENSP00000532177.1

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

African (AFR) AF: 0.00215 AC: 67 AN: 31094

American (AMR) AF: 0.0102 AC: 440 AN: 43198

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 900 AN: 25144

East Asian (EAS) AF: 0.0000513 AC: 2 AN: 39002

South Asian (SAS) AF: 0.00203 AC: 167 AN: 82360

European-Finnish (FIN) AF: 0.00488 AC: 215 AN: 44064

Middle Eastern (MID) AF: 0.0170 AC: 67 AN: 3944

European-Non Finnish (NFE) AF: 0.0129 AC: 12888 AN: 1002874

Other (OTH) AF: 0.0115 AC: 647 AN: 56034

GnomAD4 genome AF: 0.00957 AC: 1457 AN: 152304 Hom.: 18 Cov.: 32 AF XY: 0.00894 AC XY: 666 AN XY: 74472

African (AFR) AF: 0.00236 AC: 98 AN: 41574

American (AMR) AF: 0.0151 AC: 231 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 923 AN: 68024

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0119 Hom.: 26

Bravo AF: 0.0105

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

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

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Thrombophilia due to thrombin defect (12)
7	-	-	not provided (7)
3	-	-	Congenital prothrombin deficiency (4)
1	-	-	Congenital prothrombin deficiency;C0948008:Ischemic stroke;C3160733:Thrombophilia due to thrombin defect;C3280672:Pregnancy loss, recurrent, susceptibility to, 2 (1)
-	1	-	Pregnancy loss, recurrent, susceptibility to, 2 (2)
-	-	-	Cerebral palsy (1)
-	-	-	Ischemic stroke (1)
-	-	-	Thrombophilia caused by F2 prothrombin deficiency (1)
-	-	-	Venous thromboembolism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.1
DANN	Benign	0.76
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1799963; hg19: chr11-46761055;