11-46723453-C-T

Position:

chr11-46723453-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 links:

F2 (HGNC:):

F2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a peptide Activation peptide fragment 1 (size 154) in uniprot entity THRB_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000506.5

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 [Likely_benign]. Clinvar id is 256317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46723453-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
F2	NM_000506.5 linkuse as main transcript	c.494C>T	p.Thr165Met	missense_variant	6/14	ENST00000311907.10	NP_000497.1	P00734

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
F2	ENST00000311907.10 linkuse as main transcript	c.494C>T	p.Thr165Met	missense_variant	6/14	1	NM_000506.5	ENSP00000308541.5	P00734
F2	ENST00000530231.5 linkuse as main transcript	c.494C>T	p.Thr165Met	missense_variant	6/14	5		ENSP00000433907.1	E9PIT3
F2	ENST00000442468.1 linkuse as main transcript	c.464C>T	p.Thr155Met	missense_variant	6/8	3		ENSP00000387413.1	C9JV37
F2	ENST00000490274.1 linkuse as main transcript	n.274C>T		non_coding_transcript_exon_variant	1/2	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

GnomAD3 exomes

AF:

0.212

AC:

53214

AN:

251308

Hom.:

8772

AF XY:

0.204

AC XY:

27660

AN XY:

135850

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 SAS exome

AF:

0.202

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

Gnomad4 AFR exome

AF:

0.0227

Gnomad4 AMR exome

AF:

0.379

Gnomad4 ASJ exome

AF:

0.0762

Gnomad4 EAS exome

AF:

0.606

Gnomad4 SAS exome

AF:

0.208

Gnomad4 FIN exome

AF:

0.230

Gnomad4 NFE exome

AF:

0.136

Gnomad4 OTH exome

AF:

0.154

GnomAD4 genome

AF:

0.141

AC:

21466

AN:

152118

Hom.:

2467

Cov.:

AF XY:

0.151

AC XY:

11239

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0309

Gnomad4 AMR

AF:

0.237

Gnomad4 ASJ

AF:

0.0795

Gnomad4 EAS

AF:

0.591

Gnomad4 SAS

AF:

0.211

Gnomad4 FIN

AF:

0.249

Gnomad4 NFE

AF:

0.136

Gnomad4 OTH

AF:

0.123

Alfa

AF:

0.143

Hom.:

4432

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 14656880, 23029076) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Thrombophilia due to thrombin defect

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

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;.;.

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over