Example 1 is a single base exchange that has been found in a homozygous state and with a high frequency in the 1000Genomes Project (TGP).
The variant lies in an extragenic part that has only little function annotated (as CTCF binding site) in any of the used databases. In addition, no further
feature was found according to RegulationSpotter definitions such as DNAse hypersensitivity, histone modifications or
transcription start sites. Only phyloP / phastCons scores are obtained, both with low values showing that the
position is not conserved.
Due to this combined evidence, RegulationSpotter calculated a very low score (3.3) and assigned this variant as polymorphism.
The detected single base exchange is not annotated in either ExAc or 1000G. However, it is a known disease causing variant in
ClinVar and HGMD responsible for Glycosylphosphatidylinositol deficiency. Because it is a known disease causing mutation, it
is denoted by RegulationSpotter as such.
Independent of this classification due to its presence in disease databases,
RegulationSpotter calculates the X-score based on the amount of evidence that the variant is located in a regulatory region.
Available annotations implicate that the region the variant is located in is a Promoter, as it is also annotated in Ensembl Regulation.
It also meets the
RegulationSpotter criteria of a Promoter by position (500bp upstream / 50bp downstream) and shows up with with overlapping
DNase I and H3K4me3 marks, which are indicative of an active promoter. In detail, there are several other histone modifications and TFBS in this region.
The probable functional importance of this location is further emphasized by the relatively high PhyloP/ PhastCons conservation values.
Taken together, these annotations account for a relatively high total X-score for this variant of 116.4.
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Dominik Seelow (dominik.seelow AT charite.de).
We also appreciate hearing about your general experiences using RegulationSpotter.