Fix frameshift conversion failure

[totakke]

fixes #58

(require '[varity.vcf-to-hgvs :as v2h])

(v2h/vcf-variant->hgvs {:chr "chr5", :pos 112175534, :ref "AGTGGCAT", :alt "A"}
                        "path/to/hg19.fa" "path/to/refGene.txt.gz")
;;=> ({:coding-dna #clj-hgvs/hgvs "NM_001127511:c.4190_4196delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1397Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001127510:c.4244_4250delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1415Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354897:c.4274_4280delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1425Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354896:c.4298_4304delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1433Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354906:c.3395_3401delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1132Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354895:c.4244_4250delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1415Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354905:c.3764_3770delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1255Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354903:c.3941_3947delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1314Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354902:c.3971_3977delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1324Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354901:c.4067_4073delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1356Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354900:c.4121_4127delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1374Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354904:c.3866_3872delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1289Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354899:c.4160_4166delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1387Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_001354898:c.4169_4175delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1390Ifs*2"}
;;    {:coding-dna #clj-hgvs/hgvs "NM_000038:c.4244_4250delGTGGCAT",
;;     :protein #clj-hgvs/hgvs "p.S1415Ifs*2"})

I confirmed lein test :all passed.

[codecov]

Codecov Report

Merging #59 (ef5b988) into master (b6bc691) will decrease coverage by 0.02%.
The diff coverage is 0.00%.

@@            Coverage Diff             @@
##           master      #59      +/-   ##
==========================================
- Coverage   45.65%   45.63%   -0.03%     
==========================================
  Files          16       16              
  Lines        1969     1970       +1     
  Branches       60       60              
==========================================
  Hits          899      899              
- Misses       1010     1011       +1     
  Partials       60       60              

Impacted Files	Coverage Δ
src/varity/vcf_to_hgvs/protein.clj	28.15% <0.00%> (-0.09%)	⬇️

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[totakke]

The fs-ter-subsitution detection added by #15 is insufficient because varity.vcf-to-hgvs.common/diff-bases considers right-side commons as well as left-side commons. In this case,

(require '[varity.vcf-to-hgvs.common :refer [diff-bases]])

(diff-bases "SGI" "I")
;;=> ["SG" "" 0 1] ; [pref-only palt-only offset _]

So (empty? palt-only) cannot detect frameshift in the changed proteins and wrongly detect it as fs-ter-substitution. A direct comparison between pref and palt is needed.

[k-kom]

Does that mean :fs-ter-substitution had been correct for (diff-bases "SGI" "S") but not for (diff-bases "SGI" "I")?

[totakke]

Yes. If the ref proteins ...SGIXXXX... change into the alt proteins ...S*YYYY..., that is substitution of G and *, not frameshift.

In #58 case, the ref proteins ...SGIXXXX... change into the alt proteins ...I*YYYY.... That is frameshift caused by the change of SGI to I. The previous implementation using diff-bases result wrongly detect it as substitution because the alt protein I correspondes to the right-side of the ref proteins SGI.

[k-kom]

Thanks. That makes sense!

[totakke]

A conversion case of #58 on hg38 assembly.

[federkasten]

LGTM. Thanks for your quick investigation and fix.

[k-kom]

Thank you for the fix and explanation. LGTM