chr11-46723421-G-GT

Variant names:

• chr11-46723421-G-GT
• rs387906522
• NM_000506.5:c.462_463insT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000506.5(F2):​c.462_463insT​(p.Asn155fs) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. N155N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: F2 NM_000506.5 frameshift, stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.11
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-46723421-G-GT is Pathogenic according to our data. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46723421-G-GT is described in CliVar as Pathogenic. Clinvar id is 13309.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5	c.462_463insT	p.Asn155fs	frameshift_variant, stop_gained	Exon 6 of 14	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.462_463insT	p.Asn155fs	frameshift_variant, stop_gained	Exon 6 of 14	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.462_463insT	p.Asn155fs	frameshift_variant, stop_gained	Exon 6 of 14	5		ENSP00000433907.1
F2	ENST00000442468.1	c.432_433insT	p.Asn145fs	frameshift_variant, stop_gained	Exon 6 of 8	3		ENSP00000387413.1
F2	ENST00000490274.1	n.242_243insT		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital prothrombin deficiency Pathogenic:1

Jun 20, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs387906522; hg19: chr11-46744971;