chr11-46723453-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000506.5(F2):c.494C>T(p.Thr165Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,613,858 control chromosomes in the GnomAD database, including 28,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T165T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 2467 hom., cov: 32)

Exomes 𝑓: 0.16 ( 25819 hom. )

Consequence

F2
NM_000506.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.246

Publications

90 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 -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.1083 (below the threshold of 3.09). Trascript score misZ: 2.7629 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital prothrombin deficiency, thrombophilia due to thrombin defect.

BP4

Computational evidence support a benign effect (MetaRNN=2.9876828E-4).

BP6

Variant 11-46723453-C-T is Benign according to our data. Variant chr11-46723453-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5 link	c.494C>T	p.Thr165Met	missense_variant	Exon 6 of 14	ENST00000311907.10	NP_000497.1	P00734

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F2	ENST00000311907.10 link	c.494C>T	p.Thr165Met	missense_variant	Exon 6 of 14	1	NM_000506.5	ENSP00000308541.5	P00734
F2	ENST00000530231.5 link	c.494C>T	p.Thr165Met	missense_variant	Exon 6 of 14	5		ENSP00000433907.1	E9PIT3
F2	ENST00000442468.1 link	c.464C>T	p.Thr155Met	missense_variant	Exon 6 of 8	3		ENSP00000387413.1	C9JV37
F2	ENST00000490274.1 link	n.274C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21451

AN:

152000

Hom.:

2455

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0310

Gnomad AMI

AF:

0.0802

Gnomad AMR

AF:

0.236

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.590

Gnomad SAS

AF:

0.211

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.126

GnomAD2 exomes

AF:

0.212

AC:

53214

AN:

251308

AF XY:

0.204

show subpopulations

Gnomad AFR exome

AF:

0.0293

Gnomad AMR exome

AF:

0.400

Gnomad ASJ exome

AF:

0.0759

Gnomad EAS exome

AF:

0.607

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.156

GnomAD4 exome

AF:

0.161

AC:

235335

AN:

1461740

Hom.:

25819

Cov.:

AF XY:

0.161

AC XY:

117110

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0227

AC:

761

AN:

33478

American (AMR)

AF:

0.379

AC:

16926

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0762

AC:

1992

AN:

26136

East Asian (EAS)

AF:

0.606

AC:

24073

AN:

39696

South Asian (SAS)

AF:

0.208

AC:

17939

AN:

86254

European-Finnish (FIN)

AF:

0.230

AC:

12297

AN:

53388

Middle Eastern (MID)

AF:

0.112

AC:

648

AN:

5768

European-Non Finnish (NFE)

AF:

0.136

AC:

151401

AN:

1111928

Other (OTH)

AF:

0.154

AC:

9298

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

11548

23097

34645

46194

57742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5818

11636

17454

23272

29090

<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:

0.141

AC:

21466

AN:

152118

Hom.:

2467

Cov.:

AF XY:

0.151

AC XY:

11239

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0309

AC:

1284

AN:

41564

American (AMR)

AF:

0.237

AC:

3614

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

276

AN:

3472

East Asian (EAS)

AF:

0.591

AC:

3031

AN:

5130

South Asian (SAS)

AF:

0.211

AC:

1017

AN:

4812

European-Finnish (FIN)

AF:

0.249

AC:

2637

AN:

10570

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9240

AN:

67984

Other (OTH)

AF:

0.123

AC:

260

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

859

1719

2578

3438

4297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<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:

0.146

Hom.:

8864

Bravo

AF:

0.139

TwinsUK

AF:

0.131

AC:

484

ALSPAC

AF:

0.139

AC:

534

ESP6500AA

AF:

0.0343

AC:

151

ESP6500EA

AF:

0.128

AC:

1097

ExAC

AF:

0.197

AC:

23903

Asia WGS

AF:

0.312

AC:

1083

AN:

3478

EpiCase

AF:

0.124

EpiControl

AF:

0.117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital prothrombin deficiency

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 14656880, 23029076) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thrombophilia due to thrombin defect

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

6.9

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.093

T;T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.17

T;T;T

MetaRNN

Benign

0.00030

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.2

M;.;.

PhyloP100

0.25

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.053

Sift

Benign

0.039

.;.;D

Sift4G

Benign

0.10

T;T;T

Polyphen

0.25

B;.;.

Vest4

0.095

MPC

0.66

ClinPred

0.0020

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.64

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over