chr11-46739326-G-T

Variant names:

• chr11-46739326-G-T
• rs387907201
• NM_000506.5:c.1787G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000506.5(F2):​c.1787G>T​(p.Arg596Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R596Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: F2 NM_000506.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.88
• Publications: 30 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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000506.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-46739326-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 692073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.1083 (below the threshold of 3.09). Trascript score misZ: 2.7629 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital prothrombin deficiency, thrombophilia due to thrombin defect.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 11-46739326-G-T is Pathogenic according to our data. Variant chr11-46739326-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 31922.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.1787G>T	p.Arg596Leu	missense_variant	Exon 14 of 14	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.1787G>T	p.Arg596Leu	missense_variant	Exon 14 of 14	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.1670G>T	p.Arg557Leu	missense_variant	Exon 14 of 14	5		ENSP00000433907.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Thrombophilia due to thrombin defect Pathogenic:1 Other:1

Jun 21, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.78	N;.
PhyloP100		6.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;.
Sift4G	Uncertain	0.029	D;D
Vest4		0.84
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907201; hg19: chr11-46760876;