VCF annotation, logic, Annovar, VEP, snpEff

Question

[vaish01kv]

I'm trying to annotate vcf file obtained manualy. Can someone please help me with the algorithm that is behind most of the annotation tool like annovar, SnpEff, VEP & other annotation tools?

Answer 1

[Pierre Lindenbaum]

• get the transcript overlapping a variant
• get the reference sequence overlapping this transcript.
• go from 5' transcript to 3' transcript: build a virtual cDNA wild and mutated.
• translate both cDNAs
• compare the proteins, find if there is a difference at the position of the variant

[vaish01kv]

Thank you so much. This is so crisp & clear. It would be even more helpful if you can help me with questions like i) where exactly databases like 1000g plays a role? ii) calculating pathogenicity score & iii) inferring allele frequency from info field.

[vaish01kv]

Could you please elaborate? Also it would be really helpful if you get me any journal explaining this.