11-46726429-T-C

Variant names:

• chr11-46726429-T-C
• rs1799867
• NM_000506.5:c.875-69T>C

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.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
• Publications: 6 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=-0.84).
• BP6: Variant 11-46726429-T-C is Benign according to our data. Variant chr11-46726429-T-C is described in ClinVar as Benign. ClinVar VariationId 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.

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.875-69T>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.875-69T>C		intron	N/A	ENSP00000308541.5
	F2	ENST00000530231.5	TSL:5	c.875-69T>C		intron	N/A	ENSP00000433907.1
	F2	ENST00000442468.1	TSL:3	c.845-69T>C		intron	N/A	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

African (AFR) AF: 0.0226 AC: 738 AN: 32642

American (AMR) AF: 0.364 AC: 13715 AN: 37660

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 1962 AN: 25520

East Asian (EAS) AF: 0.607 AC: 22764 AN: 37486

South Asian (SAS) AF: 0.209 AC: 17056 AN: 81536

European-Finnish (FIN) AF: 0.230 AC: 11619 AN: 50428

Middle Eastern (MID) AF: 0.111 AC: 604 AN: 5458

European-Non Finnish (NFE) AF: 0.137 AC: 149520 AN: 1093582

Other (OTH) AF: 0.154 AC: 9128 AN: 59086

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

African (AFR) AF: 0.0310 AC: 1288 AN: 41484

American (AMR) AF: 0.236 AC: 3608 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0797 AC: 276 AN: 3462

East Asian (EAS) AF: 0.592 AC: 3037 AN: 5126

South Asian (SAS) AF: 0.212 AC: 1019 AN: 4814

European-Finnish (FIN) AF: 0.250 AC: 2633 AN: 10532

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

European-Non Finnish (NFE) AF: 0.136 AC: 9255 AN: 67936

Other (OTH) AF: 0.123 AC: 258 AN: 2100

Alfa AF: 0.137 Hom.: 205

Bravo AF: 0.140

Asia WGS AF: 0.314 AC: 1088 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.34
DANN	Benign	0.56
PhyloP100		-1.0
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: rs1799867; hg19: chr11-46747979;