rs5900

Positions:

• chr11-46729509-G-A
• chr11-46729509-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000506.5(F2):​c.1602G>A​(p.Pro534=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,613,962 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (22 hom., cov: 32)
  • Exomes 𝑓: 0.021 (380 hom.)
• Consequence: F2 NM_000506.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.59

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-46729509-G-A is Benign according to our data. Variant chr11-46729509-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256313.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-2.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0153 (2333/152212) while in subpopulation NFE AF= 0.0252 (1711/68002). AF 95% confidence interval is 0.0242. There are 22 homozygotes in gnomad4. There are 1098 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F2	NM_000506.5	c.1602G>A	p.Pro534=	synonymous_variant	12/14	ENST00000311907.10	NP_000497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F2	ENST00000311907.10	c.1602G>A	p.Pro534=	synonymous_variant	12/14	1	NM_000506.5	ENSP00000308541	P1
F2	ENST00000530231.5	c.1485G>A	p.Pro495=	synonymous_variant	12/14	5		ENSP00000433907

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2332 AN: 152094 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00898

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0156 AC: 3911 AN: 251364 Hom.: 48 AF XY: 0.0153 AC XY: 2075 AN XY: 135878

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.00674

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0207 AC: 30320 AN: 1461750 Hom.: 380 Cov.: 31 AF XY: 0.0204 AC XY: 14813 AN XY: 727158

Gnomad4 AFR exome AF: 0.00370

Gnomad4 AMR exome AF: 0.00758

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00292

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.0244

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0153 AC: 2333 AN: 152212 Hom.: 22 Cov.: 32 AF XY: 0.0148 AC XY: 1098 AN XY: 74412

Gnomad4 AFR AF: 0.00428

Gnomad4 AMR AF: 0.00897

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0252

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0218 Hom.: 14

Bravo AF: 0.0147

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0258

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital prothrombin deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Thrombophilia due to thrombin defect Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.33
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs5900; hg19: chr11-46751059;