rs3780379
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_004972.4(JAK2):c.3060-10485G>A variant causes a intron change. The variant allele was found at a frequency of 0.175 in 575,380 control chromosomes in the GnomAD database, including 9,628 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.16 ( 2282 hom., cov: 32)
Exomes 𝑓: 0.18 ( 7346 hom. )
Consequence
JAK2
NM_004972.4 intron
NM_004972.4 intron
Scores
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 6.92
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]
TCF3P1 (HGNC:49742): (transcription factor 3 pseudogene 1)
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
JAK2 | NM_004972.4 | c.3060-10485G>A | intron_variant | ENST00000381652.4 | NP_004963.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JAK2 | ENST00000381652.4 | c.3060-10485G>A | intron_variant | 1 | NM_004972.4 | ENSP00000371067 | P1 | |||
TCF3P1 | ENST00000423021.2 | n.1607G>A | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes AF: 0.161 AC: 24399AN: 151956Hom.: 2284 Cov.: 32
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GnomAD4 exome AF: 0.180 AC: 76363AN: 423306Hom.: 7346 Cov.: 4 AF XY: 0.179 AC XY: 41103AN XY: 229172
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GnomAD4 genome AF: 0.160 AC: 24394AN: 152074Hom.: 2282 Cov.: 32 AF XY: 0.162 AC XY: 12050AN XY: 74322
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ClinVar
Not reported inComputational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at