Strange SELENON p. outputs

[Peter-J-Freeman]

Dear Pete/Ivo,

first, on the screenshot send by Pete I do not see a clear waning, but I
might miss it.

Reagrding strange results, try e.g. NM_020451.3:c.447dup. The predicted
consequence is p.(Asp430Ter) but VV gives me
p.(Asp150_Ser152delinsTerProTer). No clue why this is given.

For other variants, e.g. NM_020451.3:c.407del p.(Ser146Ter) or
NM_020451.3:c.532del p.(Leu179Ter) I get "p.?". This is a strange resutl
and I see no where a warning on my screen. You could say the result
"p.?" is the warning but I wonder whether users will understand this.

Best regards,

    Johan

[Peter-J-Freeman]

Reagrding strange results, try e.g. NM_020451.3:c.447dup. The predicted consequence is p.(Asp430Ter).

This cannot be true.

Not sure this is right. Here are the translations

REF

MGRARPGQRGPPSPGPAAQPPAPPRRRARSLALLGALLAAAAAAAVRVCARHAEAQAAARQELALKTLGTDGLFLFSSLDTDGDMYISPEEFKPIAEKLTGSCSVTQTGVQWCSHSSLQPQLPWLNUSSCLSLLRSTPAASCEEEELPPDPSEETLTIEARFQPLLPETMTKSKDGFLGVSRLALSGLRNWTAAASPSAVFATRHFQPFLPPPGQELGEPWWIIPSELSMFTGYLSNNRFYPPPPKGKEVIIHRLLSMFHPRPFVKTRFAPQGAVACLTAISDFYYTVMFRIHAEFQLSEPPDFPFWFSPAQFTGHIILSKDATHVRDFRLFVPNHRSLNVDMEWLYGASESSNMEVDIGYIPQMELEATGPSVPSVILDEDGSMIDSHLPSGEPLQFVFEEIKWQQELSWEEAARRLEVAMYPFKKVSYLPFTEAFDRAKAENKLVHSILLWGALDDQSCUGSGRTLRETVLESSPILTLLNESFISTWSLVKELEELQNNQENSSHQKLAGLHLEKYSFPVEMMICLPNGTVVHHINANYFLDITSVKPEEIESNLFSFSSTFEDPSTATYMQFLKEGLRRGLPLLQP*

VAR

MGRARPGQRGPPSPGPAAQPPAPPRRRARSLALLGALLAAAAAAAVRVCARHAEAQAAARQELALKTLGTDGLFLFSSLDTDGDMYISPEEFKPIAEKLTGSCSVTQTGVQWCSHSSLQPQLPWLNUSSCLSLLRSTPAASCEEEELPPUP*

The variation therefore happens at position 150 and is a D>U which explains the p.(Asp150_Ser152delinsTerProTer). It should be p.(Asp150_Ser152delinsSelProTer)

The Sel conversion was ignored.

[Peter-J-Freeman]

So far

import json
import VariantValidator
vval = VariantValidator.Validator()
variant = "NM_020451.3:c.447dup"
genome_build = 'GRCh38'
select_transcripts = 'all'
transcript_set = 'refseq'
validate = vval.validate(variant, genome_build, select_transcripts, transcript_set, lovd_syntax_check=True)
validation = validate.format_as_dict(with_meta=True)
print(json.dumps(validation, sort_keys=True, indent=4, separators=(',', ': ')))

        "hgvs_predicted_protein_consequence": {
            "lrg_slr": "LRG_857p1:p.(D150_S152delinsUP*)",
            "lrg_tlr": "LRG_857p1:p.(Asp150_Ser152delinsSecProTer)",
            "slr": "NP_065184.2:p.(D150_S152delinsUP*)",
            "tlr": "NP_065184.2:p.(Asp150_Ser152delinsSecProTer)"
        },

But to me this is a frame shift, especially given the 1 bp dup in the NM_

[Peter-J-Freeman]

So, corrected is

        "hgvs_predicted_protein_consequence": {
            "lrg_slr": "LRG_857p1:p.D150Ufs*2",
            "lrg_tlr": "LRG_857p1:p.Asp150SecfsTer2",
            "slr": "NP_065184.2:p.D150Ufs*2",
            "tlr": "NP_065184.2:p.Asp150SecfsTer2"
        },

[Peter-J-Freeman]

Other variants in this issue also now fixed.

to do - Insertions

[Peter-J-Freeman]

During fixing of this issue, I have now switched the VV p. translation code away from vv_HGVS to VV internal code.

The following failures need addressing

FAILED tests/test_inputs.py::TestVariantsAuto::test_issue_214b - AssertionError: assert 'NP_036222.3:p.(Ser10delinsLysTer)' in 'NP_036222.3:p.(Ser10_Glu11delinsLysTer)'
FAILED tests/test_inputs.py::TestVariantsAuto::test_issue_214c - AssertionError: assert 'NP_733765.1:p.(Gln259delinsProAlaTer)' in 'NP_733765.1:p.(Gln259_Ser261delinsProAlaTer)'
FAILED tests/test_inputs.py::TestVariantsAuto::test_variant77 - AssertionError: assert {'tlr': 'NP_116179.2:p.(Ter48ProextTer4)', 'slr': 'NP_116179.2:p.(*48Pext*4)'} == {'tlr': 'NP_116179.2:p.(Pro44_Pro47dup)', 'slr': 'NP_116179.2:p.(P44_P47dup)'}
  
  Differing items:
  {'slr': 'NP_116179.2:p.(*48Pext*4)'} != {'slr': 'NP_116179.2:p.(P44_P47dup)'}
  {'tlr': 'NP_116179.2:p.(Ter48ProextTer4)'} != {'tlr': 'NP_116179.2:p.(Pro44_Pro47dup)'}
  
  Full diff:
    {
  -     'slr': 'NP_116179.2:p.(P44_P47dup)',
  ?                              --------
  +     'slr': 'NP_116179.2:p.(*48Pext*4)',
  ?                            +++ ++++
  -     'tlr': 'NP_116179.2:p.(Pro44_Pro47dup)',
  ?                                ----------
  +     'tlr': 'NP_116179.2:p.(Ter48ProextTer4)',
  ?                            +++++   ++++++
    }
FAILED tests/test_inputs.py::TestVariantsAuto::test_variant279 - AssertionError: assert {'tlr': 'NP_861967.1:p.(Ter271ArgextTer2)', 'slr': 'NP_861967.1:p.(*271Rext*2)'} == {'tlr': 'NP_861967.1:p.(Arg269_Arg270dup)', 'slr': 'NP_861967.1:p.(R269_R270dup)'}
  
  Differing items:
  {'slr': 'NP_861967.1:p.(*271Rext*2)'} != {'slr': 'NP_861967.1:p.(R269_R270dup)'}
  {'tlr': 'NP_861967.1:p.(Ter271ArgextTer2)'} != {'tlr': 'NP_861967.1:p.(Arg269_Arg270dup)'}
  
  Full diff:
    {
  -     'slr': 'NP_861967.1:p.(R269_R270dup)',
  ?                            ^^^^^^  ^^^^
  +     'slr': 'NP_861967.1:p.(*271Rext*2)',
  ?                            ^  ^^^^^^^
  -     'tlr': 'NP_861967.1:p.(Arg269_Arg270dup)',
  +     'tlr': 'NP_861967.1:p.(Ter271ArgextTer2)',
    }
FAILED tests/test_variantformatter_inputs.py::TestVFvariantsAuto::test_variant26 - AssertionError: assert 'NP_116179.2:p.(Ter48ProextTer4)' == 'NP_116179.2:p.(Pro44_Pro47dup)'
  
  - NP_116179.2:p.(Pro44_Pro47dup)
  + NP_116179.2:p.(Ter48ProextTer4)
FAILED tests/test_variantformatter_inputs.py::TestVFvariantsAuto::test_variant62 - AssertionError: assert 'NP_055935.4:p.(Ter528LeuextTer1)' == 'NP_055935.4:p.(Leu527dup)'
  
  - NP_055935.4:p.(Leu527dup)
  + NP_055935.4:p.(Ter528LeuextTer1)
FAILED tests/test_variantformatter_inputs.py::TestVFvariantsAuto::test_variant151 - AssertionError: assert 'NP_861968.1:p.(Ter229ArgextTer2)' == 'NP_861968.1:p.(Arg227_Arg228dup)'
  
  - NP_861968.1:p.(Arg227_Arg228dup)
  + NP_861968.1:p.(Ter229ArgextTer2)
=========================================================================================== 7 failed in 38.08s ============================================================================================
(vvenv) e05374pc@B-LOSX4LHQF variantValidator % 

Documenting here for discussion. Will feed back soon

[Peter-J-Freeman]

For variant NM_032790.3:c.131_132insCCCGCCACCGCC
https://www.ncbi.nlm.nih.gov/protein/NP_116179.2?report=fasta

Ref: MHPEPAPPPSRSSPELPPSGGSTTSGSRRSRRRSGDGEPPGA**PPPPP**SAVTYPDWIGQSYSEVMSLNEHSMQALSWRKLYLSRAKLKASSRTSALLSGFAMVAMVEVQLDADHDYPPGLLIAFSACTTVLVAVHLFALMISTCILPNIEAVSNVHNLNSVKESPHERMHRHIELAWAFSTVIGTLLFLAEVVLLCWVKFLPLKKQPGQPRPTSKPPASGAAANVSTSGITPGQAAAIASTTIMVPFGLIFIVFAVHFYRSLVSHKTDRQFQELNELAEFARLQDQLDHRGDHPLTPGSHYA*

Our current test pass is NP_116179.2:p.(P44_P47dup) based on vv_HGVS code but VV code gives NP_116179.2:p.(Ter48ProextTer4) based on translation

Var: MHPEPAPPPSRSSPELPPSGGSTTSGSRRSRRRSGDGEPPGA**PPPPPPPPP**SAVTYPDWIGQSYSEVMSLNEHSMQALSWRKLYLSRAKLKASSRTSALLSGFAMVAMVEVQLDADHDYPPGLLIAFSACTTVLVAVHLFALMISTCILPNIEAVSNVHNLNSVKESPHERMHRHIELAWAFSTVIGTLLFLAEVVLLCWVKFLPLKKQPGQPRPTSKPPASGAAANVSTSGITPGQAAAIASTTIMVPFGLIFIVFAVHFYRSLVSHKTDRQFQELNELAEFARLQDQLDHRGDHPLTPGSHYA*

So, the VV code is incorrect currrently. Fixing

[Peter-J-Freeman]

Forced down the delins/del/ etc translation route rather than inv translation route fixed the issue

[Peter-J-Freeman]

Last 2 fails

Current test for NM_170665.3:c.775_776insCAGCTT
FAILED tests/test_inputs.py::TestVariantsAuto::test_issue_214b - AssertionError: assert 'NP_036222.3:p.(Ser10delinsLysTer)' in 'NP_036222.3:p.(Ser10_Glu11delinsLysTer)'

for NC_000012.11:g.110765502_110765503insCAGCTT
FAILED tests/test_inputs.py::TestVariantsAuto::test_issue_214c - AssertionError: assert 'NP_733765.1:p.(Gln259delinsProAlaTer)' in 'NP_733765.1:p.(Gln259_Ser261delinsProAlaTer)'

Relates to #214 so we know the tests are correct