rs3136435

Variant names:

• chr11-46720876-G-A
• rs3136435
• NM_000506.5:c.316+36G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000506.5(F2):​c.316+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 1,612,902 control chromosomes in the GnomAD database, including 8,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2948 hom., cov: 32)
  • Exomes 𝑓: 0.077 (5874 hom.)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0760
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-46720876-G-A is Benign according to our data. Variant chr11-46720876-G-A is described in ClinVar as Benign. ClinVar VariationId is 1290658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5	c.316+36G>A		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+36G>A		intron_variant	Intron 4 of 13	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.316+36G>A		intron_variant	Intron 4 of 13	5		ENSP00000433907.1
F2	ENST00000442468.1	c.286+36G>A		intron_variant	Intron 4 of 7	3		ENSP00000387413.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22541 AN: 151996 Hom.: 2937 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0769

Gnomad ASJ AF: 0.0664

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0696

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.0842 AC: 21029 AN: 249896 AF XY: 0.0789

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0640

Gnomad EAS exome AF: 0.0959

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0705

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0765 AC: 111787 AN: 1460788 Hom.: 5874 Cov.: 31 AF XY: 0.0752 AC XY: 54668 AN XY: 726662

African (AFR) AF: 0.369 AC: 12351 AN: 33468

American (AMR) AF: 0.0477 AC: 2134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0664 AC: 1736 AN: 26128

East Asian (EAS) AF: 0.0870 AC: 3453 AN: 39694

South Asian (SAS) AF: 0.0653 AC: 5628 AN: 86244

European-Finnish (FIN) AF: 0.0467 AC: 2469 AN: 52920

Middle Eastern (MID) AF: 0.0924 AC: 533 AN: 5768

European-Non Finnish (NFE) AF: 0.0703 AC: 78111 AN: 1111464

Other (OTH) AF: 0.0890 AC: 5372 AN: 60378

GnomAD4 genome AF: 0.148 AC: 22582 AN: 152114 Hom.: 2948 Cov.: 32 AF XY: 0.145 AC XY: 10799 AN XY: 74376

African (AFR) AF: 0.356 AC: 14758 AN: 41434

American (AMR) AF: 0.0768 AC: 1173 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0664 AC: 230 AN: 3466

East Asian (EAS) AF: 0.101 AC: 523 AN: 5172

South Asian (SAS) AF: 0.0555 AC: 268 AN: 4830

European-Finnish (FIN) AF: 0.0473 AC: 502 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0696 AC: 4731 AN: 68006

Other (OTH) AF: 0.131 AC: 276 AN: 2112

Alfa AF: 0.0941 Hom.: 1663

Bravo AF: 0.159

Asia WGS AF: 0.101 AC: 352 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.59
PhyloP100		-0.076
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
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: rs3136435; hg19: chr11-46742426; COSMIC: COSV61317638; COSMIC: COSV61317638;