11-46729851-T-C

Variant names:

• chr11-46729851-T-C
• rs2282687
• NM_000506.5:c.1654+290T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000506.5(F2):​c.1654+290T>C 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 152,018 control chromosomes in the GnomAD database, including 2,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (2474 hom., cov: 31)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.285
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-46729851-T-C is Benign according to our data. Variant chr11-46729851-T-C is described in ClinVar as Benign. ClinVar VariationId is 1258693.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5	c.1654+290T>C		intron_variant	Intron 12 of 13	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.1654+290T>C		intron_variant	Intron 12 of 13	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.1537+290T>C		intron_variant	Intron 12 of 13	5		ENSP00000433907.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21475 AN: 151900 Hom.: 2462 Cov.: 31

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.0796

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.124

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

GnomAD4 genome AF: 0.141 AC: 21490 AN: 152018 Hom.: 2474 Cov.: 31 AF XY: 0.151 AC XY: 11252 AN XY: 74296

African (AFR) AF: 0.0310 AC: 1285 AN: 41492

American (AMR) AF: 0.236 AC: 3608 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 276 AN: 3468

East Asian (EAS) AF: 0.593 AC: 3058 AN: 5158

South Asian (SAS) AF: 0.211 AC: 1012 AN: 4798

European-Finnish (FIN) AF: 0.249 AC: 2625 AN: 10542

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

European-Non Finnish (NFE) AF: 0.136 AC: 9261 AN: 67972

Other (OTH) AF: 0.122 AC: 257 AN: 2112

Alfa AF: 0.0964 Hom.: 269

Bravo AF: 0.140

Asia WGS AF: 0.312 AC: 1084 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.3
DANN	Benign	0.54
PhyloP100		-0.28
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: rs2282687; hg19: chr11-46751401;