rs587776431

Variant names:

• chr11-46739206-G-A
• rs3136516
• NM_000506.5:c.1726-59G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000506.5(F2):​c.1726-59G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,613,514 control chromosomes in the GnomAD database, including 197,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13994 hom., cov: 31)
  • Exomes 𝑓: 0.49 (183774 hom.)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.871
• Publications: 69 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 11-46739206-G-A is Benign according to our data. Variant chr11-46739206-G-A is described in ClinVar as Benign. ClinVar VariationId is 143996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000506.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	NM_000506.5	MANE Select	c.1726-59G>A		intron	N/A	NP_000497.1	P00734

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	ENST00000311907.10	TSL:1 MANE Select	c.1726-59G>A		intron	N/A	ENSP00000308541.5	P00734
	F2	ENST00000862106.1		c.1822-59G>A		intron	N/A	ENSP00000532165.1
	F2	ENST00000862118.1		c.1774-59G>A		intron	N/A	ENSP00000532177.1

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58279 AN: 151840 Hom.: 13989 Cov.: 31

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.424

GnomAD4 exome AF: 0.491 AC: 718264 AN: 1461554 Hom.: 183774 Cov.: 38 AF XY: 0.490 AC XY: 355996 AN XY: 727092

African (AFR) AF: 0.0809 AC: 2707 AN: 33478

American (AMR) AF: 0.406 AC: 18136 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13621 AN: 26128

East Asian (EAS) AF: 0.150 AC: 5962 AN: 39698

South Asian (SAS) AF: 0.367 AC: 31673 AN: 86250

European-Finnish (FIN) AF: 0.554 AC: 29607 AN: 53414

Middle Eastern (MID) AF: 0.450 AC: 2592 AN: 5766

European-Non Finnish (NFE) AF: 0.527 AC: 585497 AN: 1111712

Other (OTH) AF: 0.471 AC: 28469 AN: 60392

GnomAD4 genome AF: 0.384 AC: 58281 AN: 151960 Hom.: 13994 Cov.: 31 AF XY: 0.383 AC XY: 28462 AN XY: 74262

African (AFR) AF: 0.0976 AC: 4050 AN: 41486

American (AMR) AF: 0.443 AC: 6755 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1810 AN: 3472

East Asian (EAS) AF: 0.173 AC: 894 AN: 5160

South Asian (SAS) AF: 0.364 AC: 1755 AN: 4818

European-Finnish (FIN) AF: 0.548 AC: 5784 AN: 10552

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.525 AC: 35679 AN: 67914

Other (OTH) AF: 0.429 AC: 905 AN: 2108

Alfa AF: 0.457 Hom.: 31333

Bravo AF: 0.365

Asia WGS AF: 0.285 AC: 996 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital prothrombin deficiency;C0948008:Ischemic stroke;C3160733:Thrombophilia due to thrombin defect;C3280672:Pregnancy loss, recurrent, susceptibility to, 2 (1)
-	-	-	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.6
DANN	Benign	0.75
PhyloP100		0.87
Mutation Taster		=100/0	polymorphism (auto)

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: rs3136516; hg19: chr11-46760756; COSMIC: COSV56372590; COSMIC: COSV56372590;