chr11-46723439-C-T

Variant names:

• chr11-46723439-C-T
• rs3136452
• NM_000506.5:c.480C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000506.5(F2):​c.480C>T​(p.Pro160Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,614,054 control chromosomes in the GnomAD database, including 786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (413 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (373 hom.)
• Consequence: F2 NM_000506.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.30

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-46723439-C-T is Benign according to our data. Variant chr11-46723439-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F2	NM_000506.5	c.480C>T	p.Pro160Pro	synonymous_variant	Exon 6 of 14	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.480C>T	p.Pro160Pro	synonymous_variant	Exon 6 of 14	1	NM_000506.5	ENSP00000308541.5
F2	ENST00000530231.5	c.480C>T	p.Pro160Pro	synonymous_variant	Exon 6 of 14	5		ENSP00000433907.1
F2	ENST00000442468.1	c.450C>T	p.Pro150Pro	synonymous_variant	Exon 6 of 8	3		ENSP00000387413.1
F2	ENST00000490274.1	n.260C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 6100 AN: 152096 Hom.: 413 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0111 AC: 2794 AN: 251458 Hom.: 174 AF XY: 0.00804 AC XY: 1093 AN XY: 135914

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00859

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00420 AC: 6144 AN: 1461840 Hom.: 373 Cov.: 37 AF XY: 0.00362 AC XY: 2633 AN XY: 727228

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.00924

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.00992

GnomAD4 genome AF: 0.0401 AC: 6106 AN: 152214 Hom.: 413 Cov.: 32 AF XY: 0.0382 AC XY: 2847 AN XY: 74436

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0182 Hom.: 101

Bravo AF: 0.0472

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital prothrombin deficiency Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Jan 13, 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
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.26
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3136452; hg19: chr11-46744989;