chr11-46726429-T-C

Position:

• chr11-46726429-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000506.5(F2):​c.875-69T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,575,318 control chromosomes in the GnomAD database, including 26,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2470 hom., cov: 32)
  • Exomes 𝑓: 0.16 (24342 hom.)
• Consequence: F2 NM_000506.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.997

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-46726429-T-C is Benign according to our data. Variant chr11-46726429-T-C is described in ClinVar as [Benign]. Clinvar id is 1238592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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/exons	MANE	Protein	UniProt
F2	NM_000506.5	c.875-69T>C		intron_variant		ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.875-69T>C		intron_variant		1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.875-69T>C		intron_variant		5		ENSP00000433907.1
F2	ENST00000442468.1	c.845-69T>C		intron_variant		3		ENSP00000387413.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21467 AN: 151802 Hom.: 2458 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.0797

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.160 AC: 227106 AN: 1423398 Hom.: 24342 AF XY: 0.160 AC XY: 112895 AN XY: 704744

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.0769

Gnomad4 EAS exome AF: 0.607

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.141 AC: 21482 AN: 151920 Hom.: 2470 Cov.: 32 AF XY: 0.152 AC XY: 11254 AN XY: 74254

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.0797

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.123

Alfa AF: 0.137 Hom.: 205

Bravo AF: 0.140

Asia WGS AF: 0.314 AC: 1088 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.34
DANN	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs1799867; hg19: chr11-46747979;