Predicted functional impact¶
In order for a variant to pass this filter, it must have specific predicted functional impacts: - For protein-coding genes, variants must have high or moderate functional coding impact - For non-coding genes, specific functional impact terms are considered
The tables below lists the Sequence Ontology (SO) terms that are considered during variant tiering. A list of all possible SO terms can be found at the Sequence Ontology homepage.
High Impact¶
Variants with high impact sequence ontology terms will be prioritised as Tier 1 variants, providing that they pass the other variant filtering criteria.
| Sequence ontology term | Definition | Synonyms |
|---|---|---|
| SO:0001893 | A feature ablation whereby the deleted region includes a transcript feature. | Jannovar:transcript_ablation, transcript ablation, VEP:transcript_ablation |
| SO:0001574 | A splice variant that changes the 2 base pair region at the 3' end of an intron. | Jannovar:splice_acceptor_variant Seattleseq:splice-acceptor snpEff:SPLICE_SITE_ACCEPTOR splice acceptor variant VAAST:splice_acceptor_variant VEP:splice_acceptor_variant |
| SO:0001575 | A splice variant that changes the 2 base pair region at the 5' end of an intron. | Jannovar:splice_donor_variant Seattleseq:splice-donor snpEff:SPLICE_SITE_DONOR splice donor variant VAAST:splice_donor_variant VEP:splice_donor_variant |
| SO:0001587 | A sequence variant whereby at least one base of a codon is changed, resulting in a premature stop codon, leading to a shortened polypeptide. | Seattleseq:stop-gained-near-splice stop codon gained ANNOVAR:stopgain Jannovar:stop_gained nonsense nonsense codon Seattleseq:stop-gained snpEff:STOP_GAINED stop gained VAAST:stop_gained VAT:prematureStop VEP:stop_gained |
| SO:0001589 | A sequence variant which causes a disruption of the translational reading fram, because the number of nucleotides inserted or deleted is not a multiple of three. | ANNOVAR:frameshift block substitution ANNOVAR:frameshift substitution Seattleseq:frameshift-near-splice VAT:deletionFS VAT:insertionFS frameshift variant frameshift_ frameshift_coding Jannovar:frameshift_variant Seattleseq:frameshift snpEff:FRAME_SHIFT VAAST:frameshift_variant VEP:frameshift_variant |
| SO:0001578 | A sequence variant where at least one base of the terminator codon (stop) is changed, resulting in an elongated transcript | Seattleseq:stop-lost-near-splice ANNOVAR:stoploss Jannovar:stop_lost Seattleseq:stop-lost snpEff:STOP_LOST stop codon lost stop lost VAAST:stop_lost VAT:removedStop VEP:stop_lost |
| SO:0001582 | A codon variant that changes at least one base of the first codon of a transcript. | snpEff:NON_SYNONYMOUS_START initiatior codon variant initiator codon change Jannovar:initiator_codon_variant VAT:startOverlap |
| SO:0002012 | A codon variant that changes at least one base of the canonical start codon. | Jannovar:start_lost snpEff:START_LOST VEP:start_lost |
Moderate impact¶
Variants with moderate impact sequence ontology terms will be prioritised as Tier 2 variants, providing that they pass the other variant filtering criteria.
| Sequence ontology term | Definition | Synonyms |
|---|---|---|
| SO:0001889 | A feature amplification of a region containing a transcript | transcript amplification, VEP:transcript_amplification |
| SO:0001821 | An inframe non synonymous variant that inserts bases into in the coding sequence. | inframe codon gain, ANNOVAR:nonframeshift insertion, inframe increase in CDS length, inframe insertion, inframe_codon_gain, Jannovar:inframe_insertion, snpEFF:CODON_INSERTION, VAT:insertionNFS, VEP:inframe_insertion, SO:0001651 |
| SO:0001822 | An inframe non synonymous variant that deletes bases into in the coding sequence. | inframe codon loss, inframe deletion, snpEff:CODON_DELETION, ANNOVAR:nonframeshift deletion, inframe decrease in CDS length, inframe_codon_loss, Jannovar:inframe_deletion, VAT:deletionNFS, VEP:inframe_deletion, SO:0001652 |
| SO:0001583 | A sequence variant, that changes one or more bases, resulting in a different amino acid sequence but where the length is preserved. | ANNOVAR:nonsynonymous SNV, Seattleseq:missense-near-splice, VAAST:non_synonymous_codon, Jannovar:missense_variant, missense, missense codon, Seattleseq:missense, snpEff:NON_SYNONYMOUS_CODING, VAAST:missense_variant, VAT:nonsynonymous, VEP:missense_variant, SO:0001584, SO:0001783 |
| SO:0001630 | A sequence variant in which a change has occurred within the region of the splice site, either within 1-3 bases of the exon or 3-8 bases of the intron. | ANNOVAR:splicing, snpEff:SPLICE_SITE_BRANCH, snpEff:SPLICE_SITE_BRANCH_U12, Jannovar:splice_region_variant, snpEff:SPLICE_SITE_REGION, splice region variant, VAAST:splice_region_variant, VEP:splice_region_variant |
| SO:0001626 | A sequence variant where at least one base of the final codon of an incompletely annotated transcript is changed. | incomplete terminal codon variant, partial_codon, VEP:incomplete_terminal_codon_variant |
Non-coding variant impacts¶
Rare variants in non-coding genes with relevant sequence ontology terms will be prioritised as Tier 2 variants, providing that they pass the other variant filtering criteria.
| Sequence ontology term | Definition | Synonyms |
|---|---|---|
| SO:0001792 | A sequence variant that changes non-coding exon sequence in a non-coding transcript. | Seattleseq:non-coding-exon-near-splice, ANNOVAR:ncRNA_exonic, Jannovar:non_coding_transcript_exon_variant, non coding transcript exon variant, non_coding_transcript_exon_variant, Seattleseq:non-coding-exon, snpEff:non_coding_exon_variant, VEP:non_coding_transcript_exon_variant |
Transcript biotypes¶
Consequence type is considered relative to the set of GENCODE Basic transcripts on Ensembl version 90 (GRCh38) that are associated with certain biological significance (biotype) categories. All GENCODE basic transcripts associated with the gene are evaluated. The biotypes considered are listed below.
| Biotype | Description |
|---|---|
| IG_C_gene IG_D_gene IG_J_gene IG_V_gene TR_C_gene TR_D_gene TR_J_gene TR_V_gene |
Immunoglobulin (Ig) variable chain and T-cell receptor (TcR) genes imported or annotated according to the IMGT. |
| protein_coding | Contains an open reading frame (ORF). |
| nonsense_mediated_decay | If the coding sequence (following the appropriate reference) of a transcript finishes >50bp from a downstream splice site then it is tagged as NMD. If the variant does not cover the full reference coding sequence then it is annotated as NMD if NMD is unavoidable i.e. no matter what the exon structure of the missing portion is the transcript will be subject to NMD. |
| non_stop_decay | Transcripts that have polyA features (including signal) without a prior stop codon in the CDS, i.e. a non-genomic polyA tail attached directly to the CDS without 3' UTR. These transcripts are subject to degradation. |
| miRNA | Non-coding gene biotype: A small RNA (~22bp) that silences the expression of target mRNA. |
| lincRNA | Non-coding gene biotype: Transcripts that are long intergenic non-coding RNA locus with a length >200bp. Requires lack of coding potential and may not be conserved between species. |
| snRNA | Non-coding gene biotype: Small RNA molecules that are found in the cell nucleus and are involved in the processing of pre messenger RNAs. |
| snoRNA | Non-coding gene biotype: Small RNA molecules that are found in the cell nucleolus and are involved in the post-transcriptional modification of other RNAs. |