rs5898

Variant names:

• chr11-46728098-G-A
• rs5898
• NM_000506.5:c.1233G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.50

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 -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 rank	MANE	Protein	UniProt
F2	NM_000506.5	c.1233G>A	p.Pro411Pro	synonymous_variant	Exon 10 of 14	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.1233G>A	p.Pro411Pro	synonymous_variant	Exon 10 of 14	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.1233G>A	p.Pro411Pro	synonymous_variant	Exon 10 of 14	5		ENSP00000433907.1

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10033 AN: 151882 Hom.: 392 Cov.: 32

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

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.: 33 AF XY: 0.0801 AC XY: 58030 AN XY: 724818

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.: 32 AF XY: 0.0652 AC XY: 4841 AN XY: 74262

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: 85 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital prothrombin deficiency Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombophilia due to thrombin defect Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Other links and lift over

dbSNP: rs5898; hg19: chr11-46749648; COSMIC: COSV61317221; COSMIC: COSV61317221;