chr11-46723375-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000506.5(F2):c.423-7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 1,613,438 control chromosomes in the GnomAD database, including 352,437 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 24818 hom., cov: 30)

Exomes 𝑓: 0.66 ( 327619 hom. )

Consequence

F2
NM_000506.5 splice_region, intron

Scores

Splicing: ADA: 0.00002804

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.596

Publications

48 publications found

Variant links:

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

F2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 11-46723375-G-C is Benign according to our data. Variant chr11-46723375-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.687 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.423-7G>C		splice_region intron	N/A	NP_000497.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
F2	ENST00000311907.10	TSL:1 MANE Select	c.423-7G>C		splice_region intron	N/A	ENSP00000308541.5
F2	ENST00000862101.1		c.338G>C	p.Cys113Ser	missense	Exon 5 of 13	ENSP00000532160.1
F2	ENST00000862106.1		c.423-7G>C		splice_region intron	N/A	ENSP00000532165.1

Frequencies

GnomAD3 genomes

AF:

0.533

AC:

80797

AN:

151650

Hom.:

24809

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.632

Gnomad AMR

AF:

0.586

Gnomad ASJ

AF:

0.725

Gnomad EAS

AF:

0.303

Gnomad SAS

AF:

0.663

Gnomad FIN

AF:

0.626

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.693

Gnomad OTH

AF:

0.585

GnomAD2 exomes

AF:

0.602

AC:

151270

AN:

251338

AF XY:

0.620

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.496

Gnomad ASJ exome

AF:

0.722

Gnomad EAS exome

AF:

0.297

Gnomad FIN exome

AF:

0.636

Gnomad NFE exome

AF:

0.701

Gnomad OTH exome

AF:

0.669

GnomAD4 exome

AF:

0.661

AC:

966436

AN:

1461668

Hom.:

327619

Cov.:

AF XY:

0.664

AC XY:

482623

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.204

AC:

6818

AN:

33476

American (AMR)

AF:

0.510

AC:

22799

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.725

AC:

18944

AN:

26136

East Asian (EAS)

AF:

0.306

AC:

12157

AN:

39698

South Asian (SAS)

AF:

0.657

AC:

56702

AN:

86256

European-Finnish (FIN)

AF:

0.644

AC:

34399

AN:

53390

Middle Eastern (MID)

AF:

0.661

AC:

3814

AN:

5768

European-Non Finnish (NFE)

AF:

0.694

AC:

771851

AN:

1111832

Other (OTH)

AF:

0.645

AC:

38952

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

20178

40356

60534

80712

100890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19272

38544

57816

77088

96360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.532

AC:

80812

AN:

151770

Hom.:

24818

Cov.:

AF XY:

0.531

AC XY:

39400

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.218

AC:

9020

AN:

41418

American (AMR)

AF:

0.585

AC:

8932

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.725

AC:

2514

AN:

3468

East Asian (EAS)

AF:

0.303

AC:

1545

AN:

5102

South Asian (SAS)

AF:

0.664

AC:

3185

AN:

4798

European-Finnish (FIN)

AF:

0.626

AC:

6590

AN:

10524

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.693

AC:

47017

AN:

67890

Other (OTH)

AF:

0.592

AC:

1248

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1558

3117

4675

6234

7792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.665

Hom.:

24419

Bravo

AF:

0.513

Asia WGS

AF:

0.529

AC:

1843

AN:

3478

EpiCase

AF:

0.706

EpiControl

AF:

0.704

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital prothrombin deficiency (3)

not specified (3)

not provided (2)

Thrombophilia due to thrombin defect (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.33

(source)

DANN

Benign

0.50

PhyloP100

-0.60

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.0080

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over