rs5896

Variant names:

• chr11-46723453-C-T
• rs5896
• NM_000506.5:c.494C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-46723453-C-T
• chr11-46723453-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000506.5(F2):​c.494C>T​(p.Thr165Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,613,858 control chromosomes in the GnomAD database, including 28,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T165T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2467 hom., cov: 32)
  • Exomes 𝑓: 0.16 (25819 hom.)
• Consequence: F2 NM_000506.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.246
• Publications: 90 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.1083 (below the threshold of 3.09). Trascript score misZ: 2.7629 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital prothrombin deficiency, thrombophilia due to thrombin defect.
• BP4: Computational evidence support a benign effect (MetaRNN=2.9876828E-4).
• BP6: Variant 11-46723453-C-T is Benign according to our data. Variant chr11-46723453-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

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.494C>T	p.Thr165Met	missense	Exon 6 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.494C>T	p.Thr165Met	missense	Exon 6 of 14	ENSP00000308541.5	P00734
	F2	ENST00000862106.1		c.494C>T	p.Thr165Met	missense	Exon 6 of 15	ENSP00000532165.1
	F2	ENST00000862118.1		c.494C>T	p.Thr165Met	missense	Exon 6 of 14	ENSP00000532177.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21451 AN: 152000 Hom.: 2455 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.212 AC: 53214 AN: 251308 AF XY: 0.204

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.0759

Gnomad EAS exome AF: 0.607

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.161 AC: 235335 AN: 1461740 Hom.: 25819 Cov.: 38 AF XY: 0.161 AC XY: 117110 AN XY: 727174

African (AFR) AF: 0.0227 AC: 761 AN: 33478

American (AMR) AF: 0.379 AC: 16926 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0762 AC: 1992 AN: 26136

East Asian (EAS) AF: 0.606 AC: 24073 AN: 39696

South Asian (SAS) AF: 0.208 AC: 17939 AN: 86254

European-Finnish (FIN) AF: 0.230 AC: 12297 AN: 53388

Middle Eastern (MID) AF: 0.112 AC: 648 AN: 5768

European-Non Finnish (NFE) AF: 0.136 AC: 151401 AN: 1111928

Other (OTH) AF: 0.154 AC: 9298 AN: 60396

GnomAD4 genome AF: 0.141 AC: 21466 AN: 152118 Hom.: 2467 Cov.: 32 AF XY: 0.151 AC XY: 11239 AN XY: 74336

African (AFR) AF: 0.0309 AC: 1284 AN: 41564

American (AMR) AF: 0.237 AC: 3614 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 276 AN: 3472

East Asian (EAS) AF: 0.591 AC: 3031 AN: 5130

South Asian (SAS) AF: 0.211 AC: 1017 AN: 4812

European-Finnish (FIN) AF: 0.249 AC: 2637 AN: 10570

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9240 AN: 67984

Other (OTH) AF: 0.123 AC: 260 AN: 2112

Alfa AF: 0.146 Hom.: 8864

Bravo AF: 0.139

TwinsUK AF: 0.131 AC: 484

ALSPAC AF: 0.139 AC: 534

ESP6500AA AF: 0.0343 AC: 151

ESP6500EA AF: 0.128 AC: 1097

ExAC AF: 0.197 AC: 23903

Asia WGS AF: 0.312 AC: 1083 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.117

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.9
DANN	Benign	0.96
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.00030	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.25
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.053
Sift	Benign	0.039	D
Sift4G	Benign	0.10	T
Polyphen		0.25	B
Vest4		0.095
MPC		0.66
ClinPred		0.0020	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.64
Mutation Taster		=88/12	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: rs5896; hg19: chr11-46745003; COSMIC: COSV61315162; COSMIC: COSV61315162;