rs5898

Positions:

chr11-46728098-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000506.5(F2):c.1233G>A(p.Pro411Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 1,610,160 control chromosomes in the GnomAD database, including 5,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 390 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5258 hom. )

Consequence

F2
NM_000506.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.50

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]

F2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 11-46728098-G-A is Benign according to our data. Variant chr11-46728098-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46728098-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.5 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F2	NM_000506.5 linkuse as main transcript	c.1233G>A	p.Pro411Pro	synonymous_variant	10/14	ENST00000311907.10	NP_000497.1	P00734

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10 linkuse as main transcript	c.1233G>A	p.Pro411Pro	synonymous_variant	10/14	1	NM_000506.5	ENSP00000308541.5		P00734
F2	ENST00000530231.5 linkuse as main transcript	c.1233G>A	p.Pro411Pro	synonymous_variant	10/14	5		ENSP00000433907.1		E9PIT3

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10033

AN:

151882

Hom.:

392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0352

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.0489

Gnomad ASJ

AF:

0.0927

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0644

Gnomad FIN

AF:

0.0732

Gnomad MID

AF:

0.0828

Gnomad NFE

AF:

0.0896

Gnomad OTH

AF:

0.0686

GnomAD3 exomes

AF:

0.0656

AC:

16034

AN:

244568

Hom.:

714

AF XY:

0.0680

AC XY:

8978

AN XY:

131986

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.0325

Gnomad ASJ exome

AF:

0.0991

Gnomad EAS exome

AF:

0.000219

Gnomad SAS exome

AF:

0.0643

Gnomad FIN exome

AF:

0.0714

Gnomad NFE exome

AF:

0.0867

Gnomad OTH exome

AF:

0.0746

GnomAD4 exome

AF:

0.0800

AC:

116640

AN:

1458160

Hom.:

5258

Cov.:

AF XY:

0.0801

AC XY:

58030

AN XY:

724818

show subpopulations

Gnomad4 AFR exome

AF:

0.0292

Gnomad4 AMR exome

AF:

0.0342

Gnomad4 ASJ exome

AF:

0.0949

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0641

Gnomad4 FIN exome

AF:

0.0759

Gnomad4 NFE exome

AF:

0.0874

Gnomad4 OTH exome

AF:

0.0752

GnomAD4 genome

AF:

0.0660

AC:

10027

AN:

152000

Hom.:

390

Cov.:

AF XY:

0.0652

AC XY:

4841

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0352

Gnomad4 AMR

AF:

0.0489

Gnomad4 ASJ

AF:

0.0927

Gnomad4 EAS

AF:

0.00136

Gnomad4 SAS

AF:

0.0639

Gnomad4 FIN

AF:

0.0732

Gnomad4 NFE

AF:

0.0896

Gnomad4 OTH

AF:

0.0669

Alfa

AF:

0.0820

Hom.:

643

Bravo

AF:

0.0624

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital prothrombin deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Thrombophilia due to thrombin defect

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.91

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over