RNA Recommendations

Splicing Variant


Definitions

Splicing
a sequence change where, compared to a reference sequence, the normal RNA splicing pattern is altered.

Description

Variants affecting RNA splicing result in either a deletion or insertion on the RNA level and should be described as such.


Examples

  • splice acceptor site (c.650-1G>C)
    • r.650_831del
      as a consequence of a variant destroying the exon 8 splice acceptor site, the sequence from nucleotide r.650 to r.831 (exon 8) is deleted from the transcript
    • r.650_712del
      as a consequence of a variant destroying the exon 8 splice acceptor site, a new acceptor site in exon 8 (position 712 to 713) is activated and the sequence from nucleotide r.650 to r.712 is is deleted from the transcript
    • r.649_650ins650-52_650-1
      as a consequence of a variant destroying the exon 7 splice acceptor site, a new acceptor site in intron 7 (position 650-53 to 650-52) is activated and the intron 7 sequence from positions 650-53 to 650-52 is inserted in the transcript
  • splice donor site (c.831+1G>A)
    • r.650_831del
      as a consequence of a variant destroying the exon 8 splice donor site, the sequence from nucleotide r.650 to r.831 (exon 8) is deleted from the transcript
    • r.778_831del
      as a consequence of a variant destroying the exon 8 donor acceptor site, a new donor site in exon 8 (position 777 to 778) is activated and the sequence from nucleotide r.778 to r.831 is deleted from the transcript
    • r.831_832ins831+1_831+60
      as a consequence of a variant destroying the exon 8 splice donor site, a new donor site in intron 8 (position 831+60 to 831+61) is activated and the intron 8 sequence from positions 831+1 to 831+60 is inserted in the transcript
  • intron variant
    • r.649_650ins650-18_650-1
      as a consequence of an intron 7 variant (c.650-21G>T) a new stronger exon 8 splice acceptor site is created (position 650-19 to 650-18) and the intron 7 sequence from positions 650-18 to 650-1 is inserted in the transcript
    • r.831_832ins831+1_831+60
      as a consequence of an intron 8 variant (c.831+64T>A) a new stronger exon 8 splice donor site is created (position 831+60 to 831+61) and the intron 8 sequence from positions 831+1 to 831+60 is inserted in the transcript
    • r.649_650ins650-1400_650-1268
      as a consequence of an intron 7 variant (c.650-1401T>G) a new exon is created and its sequence (positions 650-1400 to 650-1268) is inserted in the transcript

Q&A

A variant changes the +1 intron sequence (GT to AT). Although I did not analyse RNA, I am quite sure that normal splicing is affected. How can I best indicate this?

Although it is not an official HGVS recommendation, many use the format "r.spl" to indicate that RNA was not analysed but splicing most probably affected. In general the format is used for variants changing the +1, +2, -2 and -1 position of an intron, i.e. affecting the GT splice donor and AG splice acceptor site (excl. GT to GC and GC to GT variants). "r.(spl?)" is frequently used to indicate normal splicing might be affected as a consequence of variants in the first or last nucleotide of an exon, the +3 to +5 intron position (splice donor site) and variants generating a new AG-dinucleotide close to the normal splice acceptor site (AG).

How can I best describe the predicted consequences at the protein level of a variant that most probably affects splicing?

The best format seems to use "p.?", meaning "I do not know what to expect at the protein level".