How to find pathogenicity of a single missense variant ?
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4.6 years ago

Hi,

Through Sanger sequencing found a missense variant in one of the exons of a gene. That mutation is not found in dbsnp database. How to predict the pathogenicity of that one missense variant?

SNP sift polyphen2 • 1.6k views
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Like your tags already hint, try SIFT or Polyphen.

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SIFT (https://sift.bii.a-star.edu.sg/www/SIFT4G_vcf_submit.html) requires a VCF file. So I created a single entry VCF file with the headers.

#CHROM  POS ID  REF ALT QUAL    FILTER  INFO    FORMAT  Sam1
chr4    18489151    .   G   A   .   .   .   GT  0/1

It din't annotate this entry and returned a empty vcf file.

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https://sift.bii.a-star.edu.sg/www/SIFT_seq_submit2.html

Use the amino acid sequence instead.

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Thanks Benn for the link for aa sequence. I took the amino acid seq from NCBI protein database and provided the amino acid change at that specific position. It completed successfully. It looks like "deleterious mutation".

amino-acid-change

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4.6 years ago

Two previous answers with more tools:

Posting a an answer in order to link up all of these old threads.

Kevin

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Thanks for sharing the links, you have listed so many tools.Great collections!!

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You're welcome but I will pass credit to my colleague who works in clinical genetics in Denmark, who devised the original listing. There are many more tools, too (upward of 70, I believe).

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4.6 years ago

In addition to tools like SIFT or Polyphen which you already included in your tags there are other calculations, such as CADD and Fathmm, which integrate lots of information for that position/variant. Another source of evidence is using transcript-expression information. dbSNP is one source, but more valuable would be to look at the frequency of the variant in gnomad.

But at the end of the day, all of these are just predictions and you'll need more genetic or functional evidence to draw any conclusions.

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