Case Report
Keywords: Germline JAK2 splice-site variant; Exon 10 skipping; Essential thrombocythemia; Tophaceous gout.
| Published: November 01, 2026 | Received: August 31, 2026 | Accepted: October 13, 2026 |
Citation: Zhu X., Long Y., Zhong L., Wu X., Xu L., Wu J. A novel germline JAK2 splice-site variant causing exon 10 skipping in a patient with an ET-like thrombocytosis phenotype and early-onset tophaceous gout. Mediterr J Hematol Infect Dis 2026, 18(1): e2026083, DOI: http://dx.doi.org/10.4084/MJHID.2026.083
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Supplementary Table 1. Annotation and ACMG/AMP-style assessment of the JAK2 c.1326+2T>A and KMT2A c.1474G>C variants
Item | JAK2 | KMT2A |
|---|---|---|
Reference genome | GRCh37 | GRCh37 |
Genomic HGVS | NC_000009.11:g.5066791T>A | NC_000011.9:g.118343348G>C |
Transcript | NM_004972.4 | NM_001197104.2 (MANE Select) |
Coding DNA change | c.1326+2T>A | c.1474G>C |
Location / type | Intron 10, +2 splice-donor position | Exon 3, missense |
Predicted protein consequence | p.? | NP_001184033.1:p.(Ala492Pro) |
Bone marrow NGS | VAF 51.4%, depth 1,219× | VAF 50.3%, depth 2,687× |
Buccal epithelial-cell NGS | VAF 48.10%, depth 526× | VAF 47.40%, depth 853× |
Inferred origin | Germline | Germline |
gnomAD v2.1.1 (exomes, PASS) | Not observed | 1/250,936 alleles (AF 3.99 × 10⁻⁶); no homozygotes; rs782462364 |
ClinVar | No entry | No entry |
In-silico prediction | SpliceAI donor loss 0.99; Pangolin splice loss 0.87 | REVEL 0.361; AlphaMissense 0.2323; PrimateAI-3D 0.70; SIFT 0.00 — discordant |
Additional annotation | Canonical +2 donor position of intron 10 | Residue located within a predicted disordered region (aa 445–585) |
RNA evidence | Complete skipping of the 112-nucleotide exon 10 confirmed by RT-PCR and bidirectional Sanger sequencing (non-quantitative) | Not applicable |
Protein / signaling evidence | Not assessed | Not assessed |
Family segregation | Offered; declined | Offered; declined |
ACMG/AMP criteria applied | PM2_Supporting | PM2_Supporting |
Criteria considered but not applied | PVS1 — although c.1326+2T>A disrupts the canonical donor site and RNA analysis demonstrated exon 10 skipping, PVS1 was not applied because loss of JAK2 function is not an established disease mechanism for JAK2-related thrombocytosis; PS3 — no protein-level or signaling evidence available; PP3 — not counted in addition to the direct RNA evidence, to avoid double-weighting the same line of evidence; PP1 — segregation data unavailable. | BP4/PP3 — discordant in-silico predictions; PS3, PP1 — not available |
Automated computational output (VarSome v13.18.7) | Likely pathogenic | Likely benign |
Diagnostic-laboratory classification | Variant of uncertain significance | Variant of uncertain significance |
Classification adopted in this report | Variant of uncertain significance | Variant of uncertain significance |
Interpretation | Germline splice-donor variant with experimentally demonstrated exon 10 skipping; a contribution to the thrombocytosis is hypothesized but unproven | Extremely rare germline missense variant with no established association with thrombocytosis, myeloid neoplasia or gout; not interpreted as an acquired clonal marker |
Notes. VAF, variant allele fraction. SpliceAI and Pangolin scores range from 0 to 1; higher values indicate a greater predicted probability of splice-site disruption. Automated outputs generated by VarSome are shown for transparency only; they are not phenotype-informed and were not adopted as the final classification in this report. Buccal epithelial cells were collected after mouth rinsing, with precautions to minimize leukocyte contamination.
Supplementary Figure 1.