rs3136456

Variant names:

• chr11-46724311-C-A
• rs3136456
• NM_000506.5:c.559+793C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-46724311-C-A
• chr11-46724311-C-G
• chr11-46724311-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000506.5(F2):​c.559+793C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 152,188 control chromosomes in the GnomAD database, including 364 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.069 (364 hom., cov: 32)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.09
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.094 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.559+793C>A		intron	N/A	NP_000497.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	ENST00000311907.10	TSL:1 MANE Select	c.559+793C>A		intron	N/A	ENSP00000308541.5
	F2	ENST00000862106.1		c.559+793C>A		intron	N/A	ENSP00000532165.1
	F2	ENST00000862118.1		c.559+793C>A		intron	N/A	ENSP00000532177.1

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10482 AN: 152070 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0548

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0690

Gnomad OTH AF: 0.0692

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0690 AC: 10494 AN: 152188 Hom.: 364 Cov.: 32 AF XY: 0.0675 AC XY: 5021 AN XY: 74396

African (AFR) AF: 0.0786 AC: 3264 AN: 41516

American (AMR) AF: 0.0507 AC: 774 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 225 AN: 3466

East Asian (EAS) AF: 0.101 AC: 524 AN: 5182

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4828

European-Finnish (FIN) AF: 0.0475 AC: 503 AN: 10586

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0689 AC: 4689 AN: 68008

Other (OTH) AF: 0.0681 AC: 144 AN: 2116

Alfa AF: 0.0650 Hom.: 646

Bravo AF: 0.0694

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0090
DANN	Benign	0.62
PhyloP100		-2.1
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: rs3136456; hg19: chr11-46745861;