Frequently Asked Questions

MetaDome is a fast and easy-to-use web server that offers an easily accessible and unique perspective that enables researchers and clinicians to interpret variants of unknown significance via 'meta-domains'; a concept that we have previously validated ( L. Wiel et al. Human Mutation, 2017 ) which makes use of protein domain homology within the human genome to transfer genetic variant information across homologous domains. MetaDome can visualize meta-domain information and gene-wide profiles of genetic tolerance.

Analyses through MetaDome can be performed by querying a gene name and desired transcript. The result is a visualization that a user may interact with to highlight positions of their interest and obtain more detailed information of those positions. This includes regional tolerance to missense variation and the presence or absence of variation at corresponding positions within homologous domains.

To get more familiar with the using MetaDome and all of it's functionality we strongly advise to start the tour.

Although we recommend using a laptop/desktop with a compatible browser for the best user experience, we designed the user interface to be useable for mobile devices as well. If you encounter any problems or see any possible improvements please contact us.

The MetaDome web server is developed and extensively tested using Google Chrome and Firefox. We recommend using one of these browsers to access all functionality. Here is a list of compatible and tested browsers:

OS	Version	Chrome	Firefox	Microsoft Edge	Microsoft IE	Safari
Linux	Ubuntu 16.04 and 18.04	70.0	63.0	n/a	n/a	n/a
MacOS	Mojave	70.0	63.0	n/a	n/a	Not supported
Windows	7 and 10	70.0	63.0	Not tested	Not supported	n/a

Although we have extensively tested MetaDome and are constantly monitoring the server for any downtime. If you do encounter problems or behaviour you did not expect. We would highly appreciate it if you could contact us.

MetaDome combines data from various public resources. The underlying data of MetaDome currently contains information from 56,319 human transcripts (GENCODE), 71,419 Pfam protein domain instances, 12,164,292 population-based genetic variants from gnomAD, and 34,076 pathogenic mutations from ClinVar.

Currently MetaDome requires a manual reannotation of the underlying data. In a future version of MetaDome is expected to schedule automatic downloading of new data releases and automatic reannotation.

MetaDome is final for its first release version. But we are still actively attempting to improve MetaDome based on feedback. If you have any improvement ideas, please contact us. Current improvements that we are working on may be found here.

For sake of high data quality we have limited the possible transcripts and genes suitable for a MetaDome Analysis to the GENCODE Basic transcripts of which the translation is identically matched with a SwissProt protein sequence. All GENCODE Basic transcripts are validated to be expressed as mRNA and all SwissProt proteins are curated by experts.

All annotated protein domains in MetaDome result from Pfam. Pfam holds a strict notion on what a protein domain is and differs to other protein domain annotation services. We have specifically chose Pfam, as the underlying method is suitable to indicate homologously identical positions across protein domains that can directly be used to transfer variant information.

The black boxes represent positions that cannot be aligned to the Pfam domain consensus. For these positions we cannot transfer variant information across homologous domains.

The tolerance is computed as a from missense over synonymous variant count ratio, which is calculated in a sliding window manner to provide a per-position indication of regional tolerance to missense variation. The variants are based on gnomAD and corrected for codon composition. For more information we suggest reading "Computing genetic tolerance and generating a tolerance landscape".

The colours are based on missense over synonymous ratio computations over the entire protein for all proteins. Here the Yellow (or neutral) is based on the average missense over synonymous ratio score that you would obtain this way and the red (intolerant) and blue (tolerant) are based on the top/bottom scores.

This corresponds to how many homologous positions are aligned to that specific position. In general we would advise to maintain a minimum of 80% alignment coverage for high quality results.