rs5900

Variant names:

• chr11-46729509-G-A
• rs5900
• NM_000506.5:c.1602G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000506.5(F2):​c.1602G>A​(p.Pro534Pro) 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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• thrombophilia due to thrombin defect

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• congenital prothrombin deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256313.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000506.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	NM_000506.5	MANE Select	c.1602G>A	p.Pro534Pro	synonymous	Exon 12 of 14	NP_000497.1	P00734

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2	ENST00000311907.10	TSL:1 MANE Select	c.1602G>A	p.Pro534Pro	synonymous	Exon 12 of 14	ENSP00000308541.5	P00734
	F2	ENST00000862106.1		c.1698G>A	p.Pro566Pro	synonymous	Exon 13 of 15	ENSP00000532165.1
	F2	ENST00000862118.1		c.1650G>A	p.Pro550Pro	synonymous	Exon 12 of 14	ENSP00000532177.1

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

GnomAD2 exomes AF: 0.0156 AC: 3911 AN: 251364 AF XY: 0.0153

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 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

African (AFR) AF: 0.00370 AC: 124 AN: 33480

American (AMR) AF: 0.00758 AC: 339 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00907 AC: 237 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00292 AC: 252 AN: 86256

European-Finnish (FIN) AF: 0.0210 AC: 1123 AN: 53392

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5768

European-Non Finnish (NFE) AF: 0.0244 AC: 27122 AN: 1111910

Other (OTH) AF: 0.0178 AC: 1074 AN: 60388

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

African (AFR) AF: 0.00428 AC: 178 AN: 41546

American (AMR) AF: 0.00897 AC: 137 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0252 AC: 1711 AN: 68002

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

Alfa AF: 0.0228 Hom.: 88

Bravo AF: 0.0147

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0258

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital prothrombin deficiency (2)
-	-	1	not specified (1)
-	1	-	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.33
DANN	Benign	0.58
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5900; hg19: chr11-46751059;