Frequently Asked Questions

MetaDome is a fast and easy-to-use web server that offers an easily accessible and unique perspective for 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 ). It makes use of protein domain homology within the human genome to transfer genetic variant information across homologous domains. MetaDome can visualise meta-domain information and gene-wide profiles of genetic tolerance.

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

To become more familiar with using MetaDome and all of its functionality, we strongly advise you to start the tour.

Although we recommend using a laptop or desktop computer with a compatible browser for the best user experience, we designed the user interface to be usable on 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 downtime, problems can still occur. If you encounter issues 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 in 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 manual reannotation of the underlying data. In a future version, MetaDome is expected to support automatic downloading of new data releases and automatic reannotation.

MetaDome has been released, but we are still actively working to improve it based on feedback. If you have any ideas for improvement, please contact us. Current improvements that we are working on can be found here.

For the sake of high data quality, we have limited the transcripts and genes suitable for MetaDome analysis to GENCODE Basic transcripts whose translation is identically matched with a Swiss-Prot protein sequence. All GENCODE Basic transcripts are validated as expressed mRNA, and all Swiss-Prot proteins are curated by experts.

All annotated protein domains in MetaDome come from Pfam. Pfam has a strict definition of what constitutes a protein domain and differs from other protein domain annotation services. We specifically chose Pfam because the underlying method is suitable for identifying homologously identical positions across protein domains that can be used directly 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.

Tolerance is computed as a 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 across the entire protein for all proteins. Yellow (neutral) is based on the average missense-over-synonymous ratio score that would be obtained in this way, while red (intolerant) and blue (tolerant) are based on the highest and lowest scores.

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