Learning to use

Genome-Phenome Analyzer: How to use

The Genome-Phenome Analyzer is the top tier of the SimulConsult products. If you have access to this version you can analyze genomes and even large copy number variations (CNV) in the clinical context.

Try this out by downloading our tiny demo (choose trio or beyond trio version), containing an anonymized patient summary PDF file and a tiny simulated variant file for a trio (proband, mother, father).

Load the patient summary into the software by starting the software and then using the menu at the right of the top black bar to choose “Load or save patient”. Load the Summary file, and then you will be offered the opportunity to load the variant file. After the file loads, you get a technical report about the variants read.

Demo video: Genome Analysis

Demo video: Genome Report

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  • Click Diagnose on the black bar, and you will see that VLDLR-related cerebellar hypoplasia is the #1 diagnosis.
  • Click the Phenotype tab to see what clinical findings were used.
  • Click the Genotype tab to see the plausible gene zygosities that were found based on the variants, the affected status of the individuals, and the severity assessments of the zygosities. Here, VLDLR gene variants (biallelic) is #1, with severity 5. Clicking that, a button “Show the 1 VLDLR variant” appears, and clicking it shows a mini variant table.
Genotype display

Mini variant table

In the mini variant table, affected individuals are named in red. Each line has a variant with sequence annotation (with ClinVar link), chromosomal position (with UCSC Genome Browser graph link and with genome assembly specified), effect and zygosity in each individual (with names derived from the variant table). Hover over a zygosity to get depth and quality scores for that individual. The basis for the severity is explained; such explanations can include functional and conservation scores, homoshares information, and other information such as high frequency or excessive de novo variants in the variant table.

Explore variants for other genes and you will see some with blue shading, indicating a variant that seems too frequent given the incidence of the disease. The type of frequency data has descriptors derived from the variant table.

Make your own variant tables by following the format at Variant table fields, using the simulated tiny variant file in this example as a guide to get started. Labs can write a script to generate a file in this format.

Some examples of the advanced features built into the analysis:

  • The Genome-Phenome Analyzer knows about pseudoautosomal genes, not just ones that produce a protein.
  • There is a detailed model of X-linked inheritance, reflecting the fact that a disease can be somewhere in-between X-linked dominant and X-linked recessive, and even have some findings of each type as in X-linked adrenoleukodystrophy, where the hormonal deficiency is recessive but the axonopathy is dominant.
  • Deprecated HGNC symbols going back to 2010 are recognized and attributed to the new HGNC symbol.

Discovery genes: sometimes the gene responsible for the illness is one not yet known to have a human clinical phenotype. Click the DNA helix button on the top black bar in the software and choose “Discovery genes”. Those with brown text are ExAC suspicious. Clicking on a gene zygosity allows you to see its mini variant table and links to helpful resources for assessing the relevance of the gene.

Discovery genes

Genome reporting: When you’ve made your decision about what testing results you want to report, select Diagnosis 1 for the disease and the gene, select the relevant variants in the mini variant table, and select clinical or lab findings as the reason for testing. We support up to 4 disease-gene diagnosis combinations. For discovery genes, there is no disease to select, but select the gene zygosity and its relevant variants. Then open the Sharing menu at the right of the top black bar and choose “Genome report”. You’ll get a “cart” of what you chose and whether it is complete and consistent. Then click “Show genome report” to see the report.