rs72550707

Positions:

• chr11-46739504-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000506.5(F2):​c.*96C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,520,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: F2 NM_000506.5 splice_region
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: -2.18

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000854 (130/152282) while in subpopulation AFR AF= 0.00301 (125/41562). AF 95% confidence interval is 0.00258. There are 0 homozygotes in gnomad4. There are 62 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.*96C>T		splice_region_variant	14/14	ENST00000311907.10	NP_000497.1
F2	NM_000506.5	c.*96C>T		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.*96C>T		splice_region_variant	14/14	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000311907.10	c.*96C>T		3_prime_UTR_variant	14/14	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.*96C>T		downstream_gene_variant		5		ENSP00000433907.1

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 149 AN: 1367754 Hom.: 0 Cov.: 21 AF XY: 0.0000891 AC XY: 61 AN XY: 684490

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.000161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000481

Gnomad4 OTH exome AF: 0.000192

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74460

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000914

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

F2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2024

The F2 c.*96C>T variant is located in the 3' untranslated region. This variant (aka C20209T) is rare and has been reported at a maximum allele frequency of only 0.30% in Africans and has not been reported in the homozygous state. Conflicting data exist for this variant with one report showing enhanced mRNA processing resulting in heightened FII protein levels and another showing decreased expression (Danckwardt et al. 2005. PubMed ID: 16689762; van der Putten et al. 2006. PubMed ID: 16796711). The c.*96C>T variant has been associated with thrombosis, but is also found in asymptomatic controls. These data suggest that the c.*96C>T may be associated with disease, but have reduced penetrance (Warshawsky et al. 2009. PubMed ID: 19522744). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Thrombophilia due to thrombin defect Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.29
DANN	Benign	0.84

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: rs72550707; hg19: chr11-46761054;