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return no-effect when ter site is inserted around ter site and fix extension determine process #115

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merged 3 commits into from
Jan 21, 2025
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return no-effect when ter site is inserted around ter site and fix extension determine process #115

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7c2971b
fix: return no-effect when ter site is inserted around ter site
nokara26 Jan 20, 2025
4610278
fix: fix protein-extension condition
nokara26 Jan 21, 2025
aaf40df
refactor: tweak ter site pos check fn
nokara26 Jan 21, 2025
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95 changes: 51 additions & 44 deletions src/varity/vcf_to_hgvs/protein.clj
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Original file line number Diff line number Diff line change
Expand Up @@ -179,8 +179,11 @@

(defn- ter-site-same-pos?
[ref-prot-seq alt-prot-seq]
(let [ter-site-pos (dec (count ref-prot-seq))]
(= \* (get alt-prot-seq ter-site-pos))))
(and (string/includes? ref-prot-seq "*")
(string/includes? alt-prot-seq "*")
(let [ref-ter-pos (count ref-prot-seq)
alt-ter-pos (inc (count (first (string/split alt-prot-seq #"\*"))))]
(= ref-ter-pos alt-ter-pos))))

(defn- cds-start-upstream?
[cds-start pos ref alt]
Expand Down Expand Up @@ -425,8 +428,12 @@
pref-only
palt-only)
ini-site-affected (ini-site-affected? ref-exon-seq alt-exon-seq)
first-diff-aa-is-ter-site (first-diff-aa-is-ter-site? base-ppos
ref-prot-seq
alt-prot-seq*)
t (cond
ref-include-from-ter-start-and-over-ter-end :frame-shift
(and ref-include-from-ter-start-and-over-ter-end
(not first-diff-aa-is-ter-site)) :frame-shift
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treat as extension when sequence is same until before ter site.

(= (+ base-ppos offset) (count ref-prot-seq)) (if (and (= "" pref-only palt-only)
(ter-site-same-pos? ref-prot-seq alt-prot-seq*))
:no-effect
Expand All @@ -443,16 +450,16 @@

:else
:frame-shift)
(and (pos? npref) (= (first palt-only) \*)) :substitution
(and (pos? npref) (= (first palt-only) \*)) (if (ter-site-same-pos? ref-prot-seq alt-prot-seq*)
:no-effect
:substitution)
(not= ref-prot-rest alt-prot-rest) (cond
(or (and (= (first alt-prot-rest) \*)
(>= nprefo npalto)
(= palt (subs pref 0 (count palt))))
(= (first palt-only) \*)) :fs-ter-substitution
ref-include-ter-site :indel
(first-diff-aa-is-ter-site? base-ppos
ref-prot-seq
alt-prot-seq*) :extension
first-diff-aa-is-ter-site :extension
:else :frame-shift)
(or (and (zero? nprefo) (zero? npalto))
(and (= nprefo 1) (= npalto 1))) :substitution
Expand Down Expand Up @@ -572,45 +579,45 @@
(coord/unknown-coordinate))))))))

(defn- protein-extension
[ppos pref palt {:keys [ref-prot-seq alt-tx-prot-seq c-ter-adjusted-alt-prot-seq ini-offset prefer-extension-for-initial-codon-alt?] :as seq-info}]
(cond
(and (not= ppos 1)
(ter-site-same-pos? ref-prot-seq c-ter-adjusted-alt-prot-seq))
(mut/protein-no-effect)
[ppos pref palt {:keys [ref-prot-seq alt-tx-prot-seq ini-offset prefer-extension-for-initial-codon-alt?] :as seq-info}]
(let [alt-prot-seq* (format-alt-prot-seq seq-info)]
(cond
(and (not= ppos 1)
(ter-site-same-pos? ref-prot-seq alt-prot-seq*))
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change c-ter-adjusted-alt-prot-seq to alt-prot-seq*

(mut/protein-no-effect)

(and (= ppos 1) (not prefer-extension-for-initial-codon-alt?))
(mut/protein-unknown-mutation)
(and (= ppos 1) (not prefer-extension-for-initial-codon-alt?))
(mut/protein-unknown-mutation)

:else
(let [[_ ins offset _] (diff-bases (or pref "") (or palt ""))
alt-prot-seq* (format-alt-prot-seq seq-info)
ini-site ((comp str first) ref-prot-seq)
first-diff-aa-info (if (= ppos 1)
{:ppos 1
:pref ini-site}
(get-first-diff-aa-info ppos
ref-prot-seq
alt-prot-seq*))
rest-seq (if (= ppos 1)
(-> alt-tx-prot-seq
(subs 0 ini-offset)
reverse
(#(apply str %)))
(subs alt-prot-seq* (:ppos first-diff-aa-info)))
alt-aa (mut/->long-amino-acid (if (= ppos 1)
(or (last ins) (first rest-seq))
(:palt first-diff-aa-info)))
alt-aa-offset (if (and (= ppos 1) (nil? (last ins))) -1 0)
new-aa-pos (some-> (string/index-of rest-seq (:pref first-diff-aa-info)) inc (+ alt-aa-offset))]
(if (and (= ppos 1) (= alt-aa "Ter"))
(mut/protein-unknown-mutation)
(mut/protein-extension (if (= ppos 1) (mut/->long-amino-acid ini-site) "Ter")
(coord/protein-coordinate (if (= ppos 1) 1 (+ ppos offset)))
alt-aa
(if (= ppos 1) :upstream :downstream)
(if new-aa-pos
(coord/protein-coordinate new-aa-pos)
(coord/unknown-coordinate)))))))
:else
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just change indent and move alt-prot-seq* let binding to line 581

(let [[_ ins offset _] (diff-bases (or pref "") (or palt ""))
ini-site ((comp str first) ref-prot-seq)
first-diff-aa-info (if (= ppos 1)
{:ppos 1
:pref ini-site}
(get-first-diff-aa-info ppos
ref-prot-seq
alt-prot-seq*))
rest-seq (if (= ppos 1)
(-> alt-tx-prot-seq
(subs 0 ini-offset)
reverse
(#(apply str %)))
(subs alt-prot-seq* (:ppos first-diff-aa-info)))
alt-aa (mut/->long-amino-acid (if (= ppos 1)
(or (last ins) (first rest-seq))
(:palt first-diff-aa-info)))
alt-aa-offset (if (and (= ppos 1) (nil? (last ins))) -1 0)
new-aa-pos (some-> (string/index-of rest-seq (:pref first-diff-aa-info)) inc (+ alt-aa-offset))]
(if (and (= ppos 1) (= alt-aa "Ter"))
(mut/protein-unknown-mutation)
(mut/protein-extension (if (= ppos 1) (mut/->long-amino-acid ini-site) "Ter")
(coord/protein-coordinate (if (= ppos 1) 1 (+ ppos offset)))
alt-aa
(if (= ppos 1) :upstream :downstream)
(if new-aa-pos
(coord/protein-coordinate new-aa-pos)
(coord/unknown-coordinate))))))))

(defn- protein-indel
[ppos pref palt {:keys [ref-prot-seq c-ter-adjusted-alt-prot-seq
Expand Down
3 changes: 3 additions & 0 deletions test/varity/vcf_to_hgvs_test.clj
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Original file line number Diff line number Diff line change
Expand Up @@ -280,6 +280,8 @@
"chr11" 125655318 "TGA" "TAT" '("p.*477Yext*17" "p.*443Yext*17" "p.*477Yext*24")
"chr10" 8074014 "C" "CATGGGTT" '("p.*445Yext*64" "p.*444Yext*64") ; not actual example (+)
"chr10" 87965468 "TC" "T" '("p.*404Eext*11" "p.*577Eext*11" "p.*207Eext*11") ; not actual example (+)
"chrX" 15823239 "ATAA" "A" '("p.*483Text*?") ; not actual example (+)
"chr13" 24421118 "CTTA" "C" '("p.*1725Vext*2") ; not actual example (-)
;; NOTE: There are very few correct examples...

;; Extension without termination site
Expand All @@ -301,6 +303,7 @@
"chr11" 14279340 "G" "A" '("p.=") ; not actual example (-)
"chr7" 55019277 "G" "GTC" '("p.=") ; not actual example (+)
"chr17" 21042835 "T" "TG" '("p.=") ; not actual example (-)
"chr13" 24421121 "A" "ATTA" '("p.=") ; not actual example (-)

;; unknown
"chr12" 40393453 "G" "A" '("p.?") ; not actual example (+)
Expand Down
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