Cellular context shapes the transcriptomic impact of somatic variants

In 26 cancer samples across three tumor types, PrismSNV/Ligo-Seq found that over 60% of candidate somatic SNVs cause significant, cell-type-specific transcriptomic displacement, with magnitude varying by more than 30%.

• Why it matters: Prioritization by recurrence or sequence annotation leaves private somatic SNVs’ molecular effects unclear, risking misinterpretation of variants that may be active only in specific cellular states.
• What they did: The team used PrismSNV and Ligo-Seq single-cell full-length transcriptome sequencing to measure transcriptomic displacement during within-cell SNV-state toggling, then tested alignment with sequence deleteriousness and clinical catalogs.
• The result: Displacement was strongest in transcriptionally plastic, less differentiated states, sequence-based deleteriousness aligned poorly, fewer than 3% of top-displacement SNVs were in ClinVar, and CD4+ T-cell SNV-gene associations shifted during activation.

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