11-46722818-T-C

Variant names:

• chr11-46722818-T-C
• rs3136447
• NM_000506.5:c.317-362T>C

Variant summary

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

The NM_000506.5(F2):​c.317-362T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,048 control chromosomes in the GnomAD database, including 4,416 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 0.22 (4416 hom., cov: 32)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.859
• Publications: 14 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5	c.317-362T>C		intron_variant	Intron 4 of 13	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.317-362T>C		intron_variant	Intron 4 of 13	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.317-362T>C		intron_variant	Intron 4 of 13	5		ENSP00000433907.1
F2	ENST00000442468.1	c.287-362T>C		intron_variant	Intron 4 of 7	3		ENSP00000387413.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33528 AN: 151930 Hom.: 4408 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.221 AC: 33541 AN: 152048 Hom.: 4416 Cov.: 32 AF XY: 0.229 AC XY: 17039 AN XY: 74332

African (AFR) AF: 0.113 AC: 4673 AN: 41504

American (AMR) AF: 0.290 AC: 4422 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3472

East Asian (EAS) AF: 0.593 AC: 3049 AN: 5138

South Asian (SAS) AF: 0.276 AC: 1330 AN: 4822

European-Finnish (FIN) AF: 0.323 AC: 3419 AN: 10576

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15333 AN: 67950

Other (OTH) AF: 0.201 AC: 424 AN: 2112

Alfa AF: 0.203 Hom.: 1323

Bravo AF: 0.217

Asia WGS AF: 0.342 AC: 1188 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.56
DANN	Benign	0.79
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3136447; hg19: chr11-46744368;