rs121918481

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The ENST00000311907.10(F2):​c.1139T>C​(p.Met380Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

F2
ENST00000311907.10 missense

Scores

9
5
4

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.74
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a disulfide_bond Interchain (between light and heavy chains) (size 146) in uniprot entity THRB_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) in ENST00000311907.10
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
Variant 11-46728004-T-C is Pathogenic according to our data. Variant chr11-46728004-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13307.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-46728004-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
F2NM_000506.5 linkuse as main transcriptc.1139T>C p.Met380Thr missense_variant 10/14 ENST00000311907.10 NP_000497.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
F2ENST00000311907.10 linkuse as main transcriptc.1139T>C p.Met380Thr missense_variant 10/141 NM_000506.5 ENSP00000308541 P1
F2ENST00000530231.5 linkuse as main transcriptc.1139T>C p.Met380Thr missense_variant 10/145 ENSP00000433907

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Congenital prothrombin deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 1992- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D;D
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
D;T
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Benign
0.55
N;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.2
D;D
REVEL
Pathogenic
0.93
Sift4G
Benign
0.66
T;T
Polyphen
1.0
D;.
Vest4
0.91
MutPred
0.88
Loss of catalytic residue at M380 (P = 0.0018);Loss of catalytic residue at M380 (P = 0.0018);
MVP
0.98
MPC
1.6
ClinPred
0.99
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.92

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121918481; hg19: chr11-46749554; API