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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
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Related Experiment Video

Updated: Aug 25, 2025

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Clinical variant interpretation and biologically relevant reference transcripts.

Fernando Pozo1, José Manuel Rodriguez2, Jesús Vázquez2,3

  • 1Bioinformatics Institute, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.

NPJ Genomic Medicine
|October 18, 2022
PubMed
Summary
This summary is machine-generated.

Choosing the right reference transcript is crucial for clinical variant interpretation. APPRIS principal and MANE Select transcripts are superior references, accurately identifying most pathogenic variants and aiding in the discovery of clinically relevant alternative isoforms.

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Area of Science:

  • Genomics
  • Bioinformatics
  • Clinical Genetics

Background:

  • Clinical variant interpretation relies heavily on selecting appropriate reference transcripts.
  • Traditionally, the longest transcript was used, but biologically supported alternatives like APPRIS principal and MANE Select are now available.

Purpose of the Study:

  • To evaluate the efficacy of APPRIS principal and MANE Select transcripts as reference sequences for clinical variant interpretation.
  • To assess the utility of TRIFID scores in predicting clinically relevant alternative transcripts.

Main Methods:

  • Comparative analysis of variant calls using different reference transcripts (longest, APPRIS principal, MANE Select).
  • Evaluation of ClinVar pathogenic variants against selected reference transcripts.
  • Application of TRIFID scores to identify and prioritize alternative isoforms.

Main Results:

  • APPRIS principal and MANE Select transcripts capture nearly all ClinVar pathogenic variants, demonstrating high concordance across 94% of coding genes.
  • A minimal number of pathogenic variants affect alternative protein products.
  • Alternative transcripts identified by high TRIFID scores are significantly more likely (approx. 700x) to harbor pathogenic variants.

Conclusions:

  • APPRIS principal and MANE Select transcripts are the optimal reference sequences for clinical variant interpretation.
  • TRIFID scores effectively predict clinically relevant alternative isoforms, enhancing variant interpretation.
  • APPRIS, MANE, and TRIFID are indispensable tools for accurate clinical variant analysis.