11-46721697-T-C

Variant names:

• chr11-46721697-T-C
• rs3136441
• NM_000506.5:c.316+857T>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.316+857T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,104 control chromosomes in the GnomAD database, including 2,500 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 (2500 hom., cov: 33)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.789
• Publications: 80 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	NM_000506.5	MANE Select	c.316+857T>C		intron	N/A	NP_000497.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	ENST00000311907.10	TSL:1 MANE Select	c.316+857T>C		intron	N/A	ENSP00000308541.5
	F2	ENST00000530231.5	TSL:5	c.316+857T>C		intron	N/A	ENSP00000433907.1
	F2	ENST00000442468.1	TSL:3	c.286+857T>C		intron	N/A	ENSP00000387413.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21557 AN: 151986 Hom.: 2488 Cov.: 33

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.252

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: 0.142 AC: 21572 AN: 152104 Hom.: 2500 Cov.: 33 AF XY: 0.152 AC XY: 11314 AN XY: 74348

African (AFR) AF: 0.0310 AC: 1288 AN: 41522

American (AMR) AF: 0.237 AC: 3628 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 276 AN: 3470

East Asian (EAS) AF: 0.594 AC: 3071 AN: 5174

South Asian (SAS) AF: 0.212 AC: 1022 AN: 4826

European-Finnish (FIN) AF: 0.252 AC: 2657 AN: 10554

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

European-Non Finnish (NFE) AF: 0.136 AC: 9262 AN: 67956

Other (OTH) AF: 0.123 AC: 260 AN: 2110

Alfa AF: 0.144 Hom.: 7127

Bravo AF: 0.140

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	-0.86
CADD	Benign	0.15
DANN	Benign	0.73
PhyloP100		-0.79
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: rs3136441; hg19: chr11-46743247; COSMIC: COSV107335264; COSMIC: COSV107335264;