Transcript Consequence Impact

Overview

Illumina Connected Annotations provides transcript consequence impacts from SnpEff.

Following definitions are used for the impact ratings as obtained from SnpEff.

Impact	Definition
high	The variant is assumed to have high (disruptive) impact in the protein, probably causing protein truncation, loss of function or triggering nonsense mediated decay.
moderate	A non-disruptive variant that might change protein effectiveness.
low	Assumed to be mostly harmless or unlikely to change protein behavior.
modifier	Usually non-coding variants or variants affecting non-coding genes, where predictions are difficult or there is no evidence of impact.

Sources

Not all consequences are rated by SnpEff, therefore Illumina Connected Annotations combines the ratings from SnpEff with those from VEP.

1. SnpEff Documentation and Codebase
2. VEP Documentation

Consequence Impacts

Following table gives the combined rating for all consequences recognized by Illumina Connected Annotations.

Consequence	SnpEff Impact	VEP Impact	Illumina Connected Annotations Impact	Comment
bidirectional_gene_fusion	high		high	SnpEff
coding_sequence_variant	low, modifier	modifier	modifier	Based on CDS
copy_number_change			modifier
copy_number_decrease			modifier
copy_number_increase			modifier
downstream_gene_variant	modifier	modifier	modifier	SnpEff + VEP
feature_elongation	modifier	high	high	VEP
feature_truncation		high	high	VEP
five_prime_duplicated_transcript			modifier
five_prime_UTR_variant	modifier	modifier	modifier	SnpEff + VEP
frameshift_variant	high	high	high	SnpEff + VEP
gene_fusion	high		high	SnpEff
incomplete_terminal_codon_variant		low	low	VEP
inframe_deletion	moderate	moderate	moderate	SnpEff + VEP
inframe_insertion	moderate	moderate	moderate	SnpEff + VEP
intron_variant	modifier	modifier	modifier	SnpEff + VEP
mature_miRNA_variant		modifier	modifier	VEP
missense_variant	moderate	moderate	moderate	SnpEff + VEP
NMD_transcript_variant		modifier	modifier	VEP
non_coding_transcript_exon_variant	modifier	modifier	modifier	SnpEff + VEP
non_coding_transcript_variant	modifier	modifier	modifier	SnpEff + VEP
protein_altering_variant		moderate	moderate	VEP
regulatory_region_ablation		modifier	modifier	VEP
regulatory_region_amplification		modifier	modifier	VEP
regulatory_region_variant	modifier	modifier	modifier	SnpEff + VEP
short_tandem_repeat_change			modifier
short_tandem_repeat_contraction			modifier
short_tandem_repeat_expansion			modifier
splice_acceptor_variant	high	high	high	SnpEff + VEP
splice_donor_variant	high	high	high	SnpEff + VEP
splice_region_variant	moderate, low	low	low	Based on SPLICE_SITE_REGION in SnpEff
start_lost	high	high	high	SnpEff + VEP
start_retained_variant	low	low	low	SnpEff + VEP
stop_gained	high	high	high	SnpEff + VEP
stop_lost	high	high	high	SnpEff + VEP
stop_retained_variant	low	low	low	SnpEff + VEP
synonymous_variant	low	low	low	SnpEff + VEP
three_prime_duplicated_transcript			modifier
three_prime_UTR_variant	modifier	modifier	modifier	SnpEff + VEP
transcript_ablation	high	high	high	SnpEff + VEP
transcript_amplification		high	high	VEP
transcript_variant	modifier		modifier	SnpEff
unidirectional_gene_fusion	high		high	SnpEff
upstream_gene_variant	modifier	modifier	modifier	SnpEff + VEP

Note:

1. For transcripts with multiple consequences, the most severe impact rating is chosen.
2. In case of consequences that do not have any impact rating from SnpEff or VEP, Illumina Connected Annotations provides modifier.

Known Issues

Known Issues

The consequence splice_polypyrimidine_tract_variant, is rated as low by VEP. However, this consequence is not annotated by Illumina Connected Annotations, therefore the impact will also not be provided.

Example Transcript

The key impact for each transcript gives the impact rating for the consequence.

{
  "variants": [
    {
      "vid": "1-1623412-T-C",
      "chromosome": "1",
      "begin": 1623412,
      "end": 1623412,
      "refAllele": "T",
      "altAllele": "C",
      "variantType": "SNV",
      "hgvsg": "NC_000001.11:g.1623412T>C",
      "transcripts": [
        {
          "transcript": "ENST00000479659.5",
          "source": "Ensembl",
          "bioType": "lncRNA",
          "introns": "2/18",
          "geneId": "ENSG00000197530",
          "hgnc": "MIB2",
          "consequence": [
            "intron_variant",
            "non_coding_transcript_variant"
          ],
          "impact": "modifier",
          "hgvsc": "ENST00000479659.5:n.288-19T>C"
        },
        {
          "transcript": "ENST00000489635.5",
          "source": "VEP",
          "bioType": "mRNA",
          "codons": "aTg/aCg",
          "aminoAcids": "M/T",
          "cdnaPos": "269",
          "cdsPos": "134",
          "exons": "3/20",
          "proteinPos": "45",
          "geneId": "ENSG00000197530",
          "hgnc": "MIB2",
          "consequence": [
            "missense_variant"
          ],
          "impact": "moderate",
          "hgvsc": "ENST00000489635.5:c.134T>C",
          "hgvsp": "ENSP00000426007.1:p.(Met45Thr)",
          "proteinId": "ENSP00000426007.1"
        }
      ]
    }
  ]
}