11-46725515-C-G

Variant names:

• chr11-46725515-C-G
• rs3136460
• NM_000506.5:c.560-344C>G

Variant summary

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

The NM_000506.5(F2):​c.560-344C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,140 control chromosomes in the GnomAD database, including 2,456 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 0.14 (2456 hom., cov: 32)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 8 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 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.560-344C>G		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.560-344C>G		intron	N/A	ENSP00000308541.5
	F2	ENST00000862106.1		c.655+169C>G		intron	N/A	ENSP00000532165.1
	F2	ENST00000862118.1		c.560-344C>G		intron	N/A	ENSP00000532177.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21368 AN: 152022 Hom.: 2444 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.0796

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.126

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

GnomAD4 genome AF: 0.141 AC: 21383 AN: 152140 Hom.: 2456 Cov.: 32 AF XY: 0.150 AC XY: 11180 AN XY: 74360

African (AFR) AF: 0.0309 AC: 1282 AN: 41548

American (AMR) AF: 0.233 AC: 3555 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 276 AN: 3466

East Asian (EAS) AF: 0.592 AC: 3053 AN: 5158

South Asian (SAS) AF: 0.211 AC: 1018 AN: 4826

European-Finnish (FIN) AF: 0.246 AC: 2596 AN: 10564

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9235 AN: 67984

Other (OTH) AF: 0.123 AC: 260 AN: 2116

Alfa AF: 0.0742 Hom.: 96

Bravo AF: 0.139

Asia WGS AF: 0.313 AC: 1086 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.68
PhyloP100		1.7
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: rs3136460; hg19: chr11-46747065;