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Human Loss of Function Transcripts

Loss of Function (LoF) transcripts in Vega are transcripts annotated for the predicted functional effects caused by loss of function single nucleotide variations (SNVs). To distinguish them from the standard Havana annotation, they are shown in a separate track on Vega, and the names of the genes / transcripts are prefixed with 'LOF:'.

884 SNVs identified as part of the pilot phase of the 1000 genomes project were subjected to manual annotation with aim of resolving (i) the structure and functional potential of the gene on the reference genome, and (ii) the potential effect of the variant on the functional potential of the transcript. Where possible, transcript models representing the functional effect of the LoF variants were constructed, and it is these that are shown in Vega. The dbSNP IDs of the SNVs are associated with the transcripts models in the database and are consequently searchable. The results of this annotation are that:

  • Nonsense SNVs and small frameshift-inducing indels introduce alternative stop codons into the CDS. These novel stop codons result in either truncations or, rarely, extensions of the reference CDS.
  • Variation at both donor and acceptor splice sites affects the complex dynamics of splicing can and can potentially lead to loss of function due to erroneous exon skipping or inclusion of non-intronic sequence (so for example this can result in the inclusion of a premature stop codon). Since predicting the consequences of splice site disruption can be difficult, particularly for splice donor sites, then where there is no additional evidence for novel splice sites then all predictions of the effect of splice junction SNVs on the functional potential of a transcript are conservative.
    • For SNVs that affect splice acceptor sites, the next confidently identifiable splice acceptor is presumed to be used. Unless there is transcriptional support for the use of an alternative downstream splice acceptor within that exon then this equates to a prediction that the exon immediately proceeding the affected splice acceptor is being skipped.
    • The impact of splice donor SNVs are more difficult to predict as they can have an effect on the splicing of 5' as well as 3' exons. As such then unless there is transcriptional evidence that covers the disrupted donor site then transcripts representing the effects of splice donor SNVs have not been created.
  • Where truncations possess the positional characteristics signalling their likely targeting by the NMD pathway, this is indicated in the transcript biotype.

The work to identify the SNVs has been published by MacArthur et al. A systematic survey of loss-of-function variants in human protein-coding genes. (Science. 2012 Feb 17;335(6070):823-8. PMID: 22344438).