A joint NCBI and EMBL-EBI transcript set for clinical genomics and research

Abstract

Comprehensive genome annotation is essential to understand the impact of clinically relevant variants. However, the absence of a standard for clinical reporting and browser display complicates the process of consistent interpretation and reporting. To address these challenges, Ensembl/GENCODE1 and RefSeq2 launched a joint initiative, the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration, to converge on human gene and transcript annotation and to jointly define a high-value set of transcripts and corresponding proteins. Here, we describe the MANE transcript sets for use as universal standards for variant reporting and browser display. The MANE Select set identifies a representative transcript for each human protein-coding gene, whereas the MANE Plus Clinical set provides additional transcripts at loci where the Select transcripts alone are not sufficient to report all currently known clinical variants. Each MANE transcript represents an exact match between the exonic sequences of an Ensembl/GENCODE transcript and its counterpart in RefSeq such that the identifiers can be used synonymously. We have now released MANE Select transcripts for 97% of human protein-coding genes, including all American College of Medical Genetics and Genomics Secondary Findings list v3.0 (ref. 3) genes. MANE transcripts are accessible from major genome browsers and key resources. Widespread adoption of these transcript sets will increase the consistency of reporting, facilitate the exchange of data regardless of the annotation source and help to streamline clinical interpretation.

Tensor Decomposition and Principal Component Analysis-Based Unsupervised Feature Extraction Outperforms State-of-the-Art Methods When Applied to Histone Modification Profiles

“…The next state-of-the-art method is HOMER, which has been used in the ENCODE project and is used for the most recent reports [25]. Since HOMER has the capability to compare five input profiles with five H3K9me3 profiles directly, this was done.…”

A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism

“…Exon 10a of DNM1 is absent from the Matched Annotation from NCBI and EMBL-EBI (MANE) Select and MANE Plus Clinical transcript sets, which are standardized for use in clinical genetics and variant interpretation. 47 Future iterations of transcript standardization may benefit from accounting for the DNM1a isoform to facilitate molecular diagnosis in individuals with exon 10a-specific disease-causing variants in DNM1 . Ultimately, given the evidence that isoforms expressing exon 10a account for the most severe features of DNM1 -related disorders, our findings illuminate the necessity of assessing the relevant transcript in clinical genetic testing in order to make accurate genetic diagnoses in individuals with possible DNM1 -related neurodevelopmental disorders.…”

Caspase-4 and -5 Biology in the Pathogenesis of Inflammatory Bowel Disease

“…Although caspase-4 and -5 are referred to as single proteins, like most genes CASP4 and CASP5 code for several variants. The proteins referred to in the above sections refer to the canonical isoforms of caspase-4 (α) and -5 (A) ( Morales et al, 2022 ). The National Centre for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database lists three CASP 4 mRNA (α, γ and X1) and six CASP 5 mRNA (A, B, C, E, F and G) transcripts ( www.ncbi.nlm.nih.gov/protein ) ( Table 1 ).…”