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Expanding the Matched Annotation from NCBI and EMBL-EBI (MANE) dataset to include MANE Select for non-coding genes 

Laboratory Genetics and Genomics
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction:
MANE Select, a representative transcript from the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration has served as a universal standard to report and exchange information about clinical variants since 2018. A MANE Select transcript represents an exact match in the exons of a RefSeq transcript and the corresponding Ensembl transcript such that two identifiers can be used synonymously. A second transcript called MANE Plus Clinical is provided for genes where the MANE Select alone is not sufficient to report known clinical variants. Transcripts are chosen based on biological criteria, match GRCh38 reference genome sequence and are expected to be stable, with updates made only due to egregious reasons.

Until recently, the MANE set covered only protein-coding genes. In recent years, clinical research has highlighted the role of non-coding genes in human disease. For example, the long non-coding RNA (lncRNA) gene MALAT1 is a suggested therapeutic target to treat multiple types of cancers, and the small nuclear RNA (snRNA) gene RNU4ATAC is implicated in RNU4ATAC Spectrum Disorder. To facilitate consistent clinical variant reporting in such well-studied non-coding genes, we have now added the first batch of MANE Select transcripts for fifty non-coding genes in MANE v1.4.



 

Methods:
The criteria used to pick a MANE Select transcript for non-coding genes include data in published literature reports, transcript expression and number of exons. Transcript ends were determined using CAGE and polyA-Seq data, when available, as described in MANE documentation webpage (https://www.ncbi.nlm.nih.gov/refseq/MANE/) and in the MANE publication (https://doi.org/10.1038/s41586-022-04558-8).

 

Results:
The current MANE dataset (v1.4) includes 19338 MANE Select transcripts for almost all of human protein-coding genes that are annotated by both RefSeq and Ensembl/GENCODE annotations, including all genes in ACMG SF v3.03. MANE Select transcripts are also available for fifty non-coding genes, as well as for sixty-two protein-coding genes that are not represented on the primary reference genome assembly. Sixty-six genes have a MANE Plus Clinical transcript. A complete list of MANE transcripts can be downloaded from MANE FTP page (https://ftp.ncbi.nlm.nih.gov/refseq/MANE/). MANE data is available from major genome browsers and from RefSeq and Ensembl/GENCODE resources, including annotation files. A track hub (https://ftp.ncbi.nlm.nih.gov/refseq/MANE/trackhub/hub.txt ) is available to help visualize MANE transcripts in genome browsers. A list of rare updates made to MANE Select transcripts is posted as a new file (MANE.GRCh38.v1.4.changed_select_accessions.txt.gz ) on the FTP page. Questions, comments or requests for MANE transcripts for specific genes may be sent to MANE-help@ncbi.nlm.nih.gov or mane-help@ebi.ac.uk.

Future plans for MANE include: 1) Adding MANE Select to additional non-coding genes and including more MANE Plus Clinical transcripts with input from clinical experts and 2) expand the MANE set to include a core set of transcripts encompassing the diversity of protein isoforms produced by a gene.

 

Conclusion:
Use of MANE Select as a universal standard to report clinical variants facilitates efficient exchange of variant data within the clinical community and reduces the potential for errors in diagnosis and variant interpretations. As MANE transcripts are designed to match GRCh38, we recommend that members of the clinical community align their workflow to GRCh38 to take full advantage of MANE Select.

Acknowledgements: The work is funded in part by the National Center for Biotechnology Information of the National Library of Medicine. Additional support is from Wellcome Trust-WT200990/Z/16/Z, EMBL-Core-Funds and NIH-U24HG007234.

 

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