rs3136435

Positions:

• chr11-46720876-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000506.5(F2):​c.316+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 1,612,902 control chromosomes in the GnomAD database, including 8,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2948 hom., cov: 32)
  • Exomes 𝑓: 0.077 (5874 hom.)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0760

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-46720876-G-A is Benign according to our data. Variant chr11-46720876-G-A is described in ClinVar as [Benign]. Clinvar id is 1290658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F2	NM_000506.5	c.316+36G>A		intron_variant		ENST00000311907.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F2	ENST00000311907.10	c.316+36G>A		intron_variant		1	NM_000506.5	P1
F2	ENST00000442468.1	c.286+36G>A		intron_variant		3
F2	ENST00000530231.5	c.316+36G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22541 AN: 151996 Hom.: 2937 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0769

Gnomad ASJ AF: 0.0664

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0696

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.0842 AC: 21029 AN: 249896 Hom.: 1593 AF XY: 0.0789 AC XY: 10660 AN XY: 135154

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0640

Gnomad EAS exome AF: 0.0959

Gnomad SAS exome AF: 0.0614

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0705

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0765 AC: 111787 AN: 1460788 Hom.: 5874 Cov.: 31 AF XY: 0.0752 AC XY: 54668 AN XY: 726662

Gnomad4 AFR exome AF: 0.369

Gnomad4 AMR exome AF: 0.0477

Gnomad4 ASJ exome AF: 0.0664

Gnomad4 EAS exome AF: 0.0870

Gnomad4 SAS exome AF: 0.0653

Gnomad4 FIN exome AF: 0.0467

Gnomad4 NFE exome AF: 0.0703

Gnomad4 OTH exome AF: 0.0890

GnomAD4 genome AF: 0.148 AC: 22582 AN: 152114 Hom.: 2948 Cov.: 32 AF XY: 0.145 AC XY: 10799 AN XY: 74376

Gnomad4 AFR AF: 0.356

Gnomad4 AMR AF: 0.0768

Gnomad4 ASJ AF: 0.0664

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.0555

Gnomad4 FIN AF: 0.0473

Gnomad4 NFE AF: 0.0696

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0861 Hom.: 942

Bravo AF: 0.159

Asia WGS AF: 0.101 AC: 352 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs3136435; hg19: chr11-46742426; COSMIC: COSV61317638; COSMIC: COSV61317638;