Example 1 is a single base exchange that has been found in a homozygous state and with a high frequency in the 1000Genomes Project data (1000G).
The variant lies in an extragenic part that has only little function annotated: H3K27me3 histone modification
in more than 3 cell types (bold print), H4K4me1 histone modification in only 1 cell type, CTCF binding site in numerous cell types.
However, taken together, these annotations are not indicative of a region with a distinct regulatory function
such as a promoter or an enhancer.
PhyloP / phastCons scores are obtained, both with low values showing that the
position is not conserved.
Due to this combined evidence, RegulationSpotter calculated a low score (6.78) and assigned this variant as polymorphism
due to its homozygous presence in the 1000G data.
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 120.64.
In case you discover bugs, have suggestions or questions, please write an e-mail to Jana Marie Schwarz (jana-marie.schwarz AT charite.de) or to
Dominik Seelow (dominik.seelow AT charite.de).
We also appreciate hearing about your general experiences using RegulationSpotter.