Thread by @thatdnaguy

#ASHG20 XZ
Annotating high-impact 5 prime untranslated region variants with the UTRannotator.
Xiaolei Zhang.
@xiaolei_gene

GitHub repo:
bit.ly/34EHExc

#ASHG20 XZ Upstream open reading frames (uORFs) can exist upstream of the main coding sequence of a protein. Interested in variants that perturb upstream open reading frames, bc uORFs have been shown to affect expression of the protein-coding gene they are associated with.

#ASHG20 XZ Overlapping uORFs have a STOP after the start of the protein coding gene (oORFs). uORF variants can be disease causing. uORFs are under strong negative selection. Stronger selection over oORFs. Match in the Kozak consensus is important and can cause LoF when altered.

#ASHG20 XZ UTRannotator is a Variant Effect Predictor (VEP) plugin to annotate uORF perturbing effects. Includes small variants( 1-5 bp SNV, indel, etc). Creation of uAUGs. Remove existing uAUGs or stops. Creating stops in existing uORF. Shifting frame of the uORF.

#ASHG20 XZ Detailed annotations -existing numbers of uORFs, Kozak consensus strength, uAUG distance to CDS, uORF subtype created or disrupted, etc.

#ASHG20 XZ Look at ClinVar variants. 91 likely pathogenic variants. 4966 likely pathogenic VUS. Annotated different changes in these variants, some of which show some potentially pathogenic effects on the uORF.

#ASHG20 XZ Looked at data from Genomics England and gnomAD. 9.7% of 5' UTR variants as uORF changing in genomics england. 7.1% in gnomAD. Called high impact if disrupted uORF with strong Kozak or disrupting uORF with translation evidence. 1.5% of de novo vars in GE, 02% gnomAD.