11-46721682-C-T

Variant names:

• chr11-46721682-C-T
• rs3136520
• NM_000506.5:c.316+842C>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.316+842C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 152,188 control chromosomes in the GnomAD database, including 80 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 0.023 (80 hom., cov: 33)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.187
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5	c.316+842C>T		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.316+842C>T		intron_variant	Intron 4 of 13	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.316+842C>T		intron_variant	Intron 4 of 13	5		ENSP00000433907.1
F2	ENST00000442468.1	c.286+842C>T		intron_variant	Intron 4 of 7	3		ENSP00000387413.1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3564 AN: 152070 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.0823

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0201

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

GnomAD4 genome AF: 0.0234 AC: 3561 AN: 152188 Hom.: 80 Cov.: 33 AF XY: 0.0252 AC XY: 1877 AN XY: 74394

African (AFR) AF: 0.00604 AC: 251 AN: 41530

American (AMR) AF: 0.0133 AC: 203 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.0823 AC: 426 AN: 5176

South Asian (SAS) AF: 0.124 AC: 599 AN: 4812

European-Finnish (FIN) AF: 0.0261 AC: 276 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1722 AN: 68004

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0276 Hom.: 179

Bravo AF: 0.0193

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.29
PhyloP100		0.19
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: rs3136520; hg19: chr11-46743232;