11-46723375-G-C

Position:

chr11-46723375-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000506.5(F2):c.423-7G>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00002804

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.596

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 256315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46723375-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F2	NM_000506.5 linkuse as main transcript	c.423-7G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000311907.10

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris
F2	ENST00000311907.10 linkuse as main transcript	c.423-7G>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000506.5	P1
F2	ENST00000442468.1 linkuse as main transcript	c.393-7G>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3
F2	ENST00000530231.5 linkuse as main transcript	c.423-7G>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
F2	ENST00000490274.1 linkuse as main transcript	n.196G>C	non_coding_transcript_exon_variant	1/2	3

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

GnomAD3 exomes

AF:

0.602

AC:

151270

AN:

251338

Hom.:

48778

AF XY:

0.620

AC XY:

84176

AN XY:

135854

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 SAS exome

AF:

0.667

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

Gnomad4 AFR exome

AF:

0.204

Gnomad4 AMR exome

AF:

0.510

Gnomad4 ASJ exome

AF:

0.725

Gnomad4 EAS exome

AF:

0.306

Gnomad4 SAS exome

AF:

0.657

Gnomad4 FIN exome

AF:

0.644

Gnomad4 NFE exome

AF:

0.694

Gnomad4 OTH exome

AF:

0.645

GnomAD4 genome

AF:

0.532

AC:

80812

AN:

151770

Hom.:

24818

Cov.:

AF XY:

0.531

AC XY:

39400

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.218

Gnomad4 AMR

AF:

0.585

Gnomad4 ASJ

AF:

0.725

Gnomad4 EAS

AF:

0.303

Gnomad4 SAS

AF:

0.664

Gnomad4 FIN

AF:

0.626

Gnomad4 NFE

AF:

0.693

Gnomad4 OTH

AF:

0.592

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

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital prothrombin deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 20, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Thrombophilia due to thrombin defect

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.33

DANN

Benign

0.50

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

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