Table 2.
Variant annotation aids the interpretation of clinical relevance
| Variant number |
Amino acid change | Chrom | Position, hg19 |
HGNC symbol |
Effect | Ensembl transcript ID |
COSMIC count, Version 86 |
COSMIC Cancer Gene Census |
gnomAD % |
1KG ALT Freq % |
UK10K ALT Freq % |
ExAC ALT % |
|
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1* | p.P72R/c.215C>G | 17 | 7579472 | TP53 | missense | ENST00000269305 | 162 | TRUE | 66 | 54 | 75 | 66 | |
| 2 | p. V73G/C.218T>G | 17 | 7579469 | TP53 | missense | ENST00000269305 | TRUE | ||||||
| 3 | p.G117R/c.349G>A | 17 | 7579338 | TP53 | missense | ENST00000269305 | TRUE | ||||||
| 4 | p.S185N/c.554G>A | 17 | 7578376 | TP53 | missense | ENST00000269305 | 1 | TRUE | 0.0004 | 0.001 | |||
| 5 | p.N210D/c.628A>G | 17 | 7578221 | TP53 | missense | ENST00000269305 | 1 | TRUE | |||||
| 6 | p.R248Q/c.743G>A | 17 | 7577538 | TP53 | missense | ENST00000269305 | 1085 | TRUE | 0.002 | 0.005 | |||
| 7 | p.R283C/c.847C>T | 17 | 7577091 | TP53 | missense | ENST00000269305 | 22 | TRUE | 0.009 | 0.008 | |||
| Variant number |
Amino acid change | GERP | phyloP | CADD | SIFT | Poly Phen2 |
Mutation Taster |
FATHMM | InterPro | ALT allele Freq % |
Clinically relevant |
||
| 1* | p.P72R/c.215C>G | <2 | 1.355 | 0.4 | T | B | T | D | 49 | No | |||
| 2 | p.V73G/c.218T>G | <2 | <1 | 0.003 | T | B | T | D | 51 | No | |||
| 3 | p.G117R/c.349G>A | 4.75 | 2.63 | 32 | D | D | D | D | P53 DNA-binding domain | 32 | Yes | ||
| 4 | p.S185N/c.554G>A | <2 | <1 | 0.4 | T | B | T | D | P53 DNA-binding domain | 40 | No | ||
| 5 | p.N210D/c.628A>G | <2 | <1 | 9.6 | T | B | T | D | P53 DNA-binding domain | 20 | No | ||
| 6 | p.R248Q/c.743G>A | 3.65 | 1.305 | 34 | D | D | D | D | P53 DNA-binding domain | 48 | Yes | ||
| 7 | p.R283C/c.847C>T | 4.01 | 1.278 | 26 | D | B | D | D | P53 DNA-biriding domain | 27 | Yes | ||
Note this this variant is listed in COSMIC with a high count, but is also reported at a high frequency in population databases and is a non-pathogenic germline variant
Abbreviations. Population databases: gnomAD, The Genome Aggregation Database, Version r2.0.2; 1KG, The 1000 Genomes Project Phase 3 V5b; UK10K, The UK10K project Version 20160215; ExAC, Exome Aggregation Consortium Version 0.3.1.
Evolutionary conservation scores: GERP, Genomic Evolutionary Rate Profiling for SNVs. The higher the score, the more evolutionarily conserved the position is. Scores ≥2 were considered conserved; phyloP conservation score for SNVs. Scores ≥1 were considered conserved.
In silico prediction tools for SNVs: CADD, A Combined Annotation Dependent Depletion score Version 1.3. The higher the score, the more deleterious the variant. A score of 20 was used as a threshold for deleteriousness; SIFT, Sorting Intolerant from Tolerant. T= tolerated, D=damaging; Polyphen2, Polymorphism Phenotyping v2. B=benign, D=probably damaging; MutationTaster, T=tolerated, D=probably damaging; FATHMM, Functional Analysis through Hidden Markov Models. T=tolerated, D=damaging. The pipeline uses dbNSFP Version 2.6 for SIFT, Polyphen2, MutationTaster and FATHMM.
InterPro: Protein sequence analysis and classification. Provides protein domain information. hg19 version from the UCSC Genome Browser.
Clinically relevant variants were conserved variants with a population frequency ≤0.1%, CADD score ≥20 and predicted to be damaging by 3 of 4 prediction tools.