11-46723375-G-C

Position:

• chr11-46723375-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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

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 (HGNC:):

ACMG classification

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	Protein	UniProt
F2	NM_000506.5	c.423-7G>C		splice_region_variant, intron_variant		ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.423-7G>C		splice_region_variant, intron_variant		1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.423-7G>C		splice_region_variant, intron_variant		5		ENSP00000433907.1
F2	ENST00000442468.1	c.393-7G>C		splice_region_variant, intron_variant		3		ENSP00000387413.1
F2	ENST00000490274.1	n.196G>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80797 AN: 151650 Hom.: 24809 Cov.: 30

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

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.: 65 AF XY: 0.664 AC XY: 482623 AN XY: 727094

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.: 30 AF XY: 0.531 AC XY: 39400 AN XY: 74160

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Congenital prothrombin deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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 provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

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	- -

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

Other links and lift over

dbSNP: rs2070852; hg19: chr11-46744925; COSMIC: COSV61315158; COSMIC: COSV61315158;