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rs77375493

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

The NM_004972.4(JAK2):c.1849G>A(p.Val617Ile) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V617F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

JAK2
NM_004972.4 missense

Scores

3
7
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.55
Variant links:
Genes affected
JAK2 (HGNC:6192): (Janus kinase 2) This gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signalling. The primary isoform of this protein has an N-terminal FERM domain that is required for erythropoietin receptor association, an SH2 domain that binds STAT transcription factors, a pseudokinase domain and a C-terminal tyrosine kinase domain. Cytokine binding induces autophosphorylation and activation of this kinase. This kinase then recruits and phosphorylates signal transducer and activator of transcription (STAT) proteins. Growth factors like TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus where they influence gene transcription. Mutations in this gene are associated with numerous inflammatory diseases and malignancies. This gene is a downstream target of the pleiotropic cytokine IL6 that is produced by B cells, T cells, dendritic cells and macrophages to produce an immune response or inflammation. Disregulation of the IL6/JAK2/STAT3 signalling pathways produces increased cellular proliferation and myeloproliferative neoplasms of hematopoietic stem cells. A nonsynonymous mutation in the pseudokinase domain of this gene disrupts the domains inhibitory effect and results in constitutive tyrosine phosphorylation activity and hypersensitivity to cytokine signalling. This gene and the IL6/JAK2/STAT3 signalling pathway is a therapeutic target for the treatment of excessive inflammatory responses to viral infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain Protein kinase 1 (size 264) in uniprot entity JAK2_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_004972.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-5073770-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14662.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=3, Pathogenic=7, Likely_pathogenic=2, Uncertain_significance=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.778
PP5
Variant 9-5073770-G-A is Pathogenic according to our data. Variant chr9-5073770-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29763.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-5073770-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
JAK2NM_004972.4 linkuse as main transcriptc.1849G>A p.Val617Ile missense_variant 14/25 ENST00000381652.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
JAK2ENST00000381652.4 linkuse as main transcriptc.1849G>A p.Val617Ile missense_variant 14/251 NM_004972.4 P1
JAK2ENST00000636127.1 linkuse as main transcriptc.1849G>A p.Val617Ile missense_variant 14/165

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Thrombocythemia 3 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 08, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
27
DANN
Uncertain
1.0
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.085
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Uncertain
0.12
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.59
T
Polyphen
0.93
.;P
Vest4
0.79
MutPred
0.59
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
0.91
MPC
0.58
ClinPred
0.95
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.49
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs77375493; hg19: chr9-5073770; COSMIC: COSV67571909; API