Uncertain ranges

[theferrit32]

No description provided.

[theferrit32]

Haven't added for c. yet. The hgvs.pymeta changes are likely similar but will need to add tests.

Can use the expressions from here: #225

[korikuzma]

@biocommons/hgvs-maintainers Would we be able to get feedback on this PR?

[github-actions]

This PR is stale because it has been open 30 days with no activity. Remove stale label or comment or this will be closed in 7 days.

[andreasprlic]

It would be great to get this PR in. Can we just make sure the "uncertain" field on BaseOffsetPosition or SimplePosition gets set correctly (and tested in the unit test)?

If we express a range in parenthesis, I'd assume we want to express that the whole range is uncertain. At least that's how I'd read the hgvs spec.

Thanks!

[andreasprlic]

LGTM

[andreasprlic]

Playing around with this branch some more I realized that g_to_c projection was not yet working. As such I had a go at enabling this. Since the behavior of this projection is somewhat undefined, the current approach picks the inner (=confident) interval of the uncertain range and uses that for the .c projection. The resulting hgvs_c string is then "confident" and not "uncertain" any longer.

[github-actions]

This PR is stale because it has been open 30 days with no activity. Remove stale label or comment or this will be closed in 7 days.

[github-actions]

This PR was closed because it has been stalled for 7 days with no activity.

[andreasprlic]

Can we work on this one on Monday during our dev session?

[andreasprlic]

@reece here are the unit tests for #225

[reece]

Note: some of the provided c. examples in #225 are most likely not valid hgvs: e.g. I think this is not valid: NM_000304.3:c.-34-?_*1140dup1657. In the current form of this PR, after g_to_c this becomes: NM_000304.3:c.(?_-34)_(*1140_?)dup.

Discussion re: representation and maintenance of precision during projection

• Andreas: Retain precision of inner and outer boundaries in g_to_c and c_to_g; see example above

From #225, clinvar 251062

• clinvar g : NC_000019.9:g.(11211022_11213339)_(11217364_11218067)dup
• clinvar c : NM_000527.5:c.(190+1_191-1)_(817+1_818-1)dup

On current #699 branch:

>>> var_g1 = parse("NC_000019.9:g.(11211022_11213339)_(11217364_11218067)dup")
>>> var_g1
SequenceVariant(ac=NC_000019.9, type=g, posedit=(11211022_11213339)_(11217364_11218067)dup, gene=None)
>>> var_c1 = am38.g_to_c(var_g1, "NM_000527.5")
>>> var_c1
SequenceVariant(ac=NM_000527.5, type=c, posedit=(?_191-1)_(817+1_?)dup, gene=None)
>>> var_g2 = am38.c_to_g(var_c1)
Traceback (most recent call last):
  Cell In[16], line 1
    var_g2 = am38.c_to_g(var_c1)
  File ~/projects/biocommons/hgvs/src/hgvs/assemblymapper.py:131 in c_to_g
    return self._maybe_normalize(var_out)
  File ~/projects/biocommons/hgvs/src/hgvs/assemblymapper.py:265 in _maybe_normalize
    return self._norm.normalize(var)
  File ~/projects/biocommons/hgvs/src/hgvs/normalizer.py:119 in normalize
    if var.posedit.pos.start.base < 0 or not is_valid_pos(var.ac, var.posedit.pos.end.base):
AttributeError: 'Interval' object has no attribute 'base'

Taking var_c1 above, new additional tests in tests/test_hgvs_sequencevariant.py (#699):

• hgvs g: NC_000019.9:g.(?11213339)(11217364_?)dup
• hgvs c: NM_000527.5:c.(?191-1)(817+1_?)dup

While these are good tests, they are not testing the same thing as the clinvar variants. We should generally try for round-trip variant projection and expect to explain cases where this isn't true.

Grammar changes

• Kyle: Address comments re: grammar in PR
• Reece: find or recreate table of grammar rules and classes [found! here]
• Kyle & Reece: collaborate on grammar and class changes to support interval of intervals

Clinvar genomic  NC_000017.10:g.(?_15133094)_(15164078_?)dup
hgvs:            NM_000304.3                 :c. (?_-34)_(*1140_?)  dup
ClinVar has: NM_000304.3(PMP22)  :c. -34-? _ *1140        dup1657

Kinds of locations

                          (190,None)
                        (190+1,None)
         (190+1       _        191-1)
(190+1 _ 191-1) _ (817+1 _ 818-1)

• Reece: Create separate issue for uncertain BaseOffset values. Done: Support uncertain BaseOffset positions #770 .

>>> v = parse("NM_000304.3(PMP22):c.-34-?_*1140dup1657")
HGVSParseError: NM_000304.3(PMP22):c.-34-?_*1140dup1657: char 25: expected a digit

-34-? is not be parsed by hgvs currently because offset = snum | (-> 0) (hgvs.pymeta:202)

Other Action Items:

• Reece: Reconcile main w/current branch
• Reschedule maintainers' meeting to discuss
• Separate issue: Add support for ? in offset. Done. See Support uncertain BaseOffset positions #770
• Reece: raise issue re: use of dup in HGVS v. real-world use by LDs.

[reece]

@andreasprlic @theferrit32 I did a bunch of surgery on project config diffs between main and this branch. They're now in sync. Tests pass, including on github (i.e., the cache is intact)

Please destroy your venv and rebuild with make devready to test.

[davmlaw]

It would be good if you could summarise the current state of things and what needs to be done.

From my quick skim - I'm worried about the silent conversion between types eg g_to_n. The HGVS spec doesn't list how conversions should be done, so we are on our own.

In g_to_n - comment is "in case of uncertain ranges, we fall back to the inner (more confident) interval"

This is a valid choice, but I argue it's not the only one.

I would argue:

• We can't convert things silently - the only possible default is to return "p.?" or "c.?" (unless we calculate all possibilities?)
• We should offer a SequenceVariant convenience method to return a new SequenceVariant object representing the certain inner interval, so clients can call g_to_n with that explicitly
• We could offer an option in mapper to do this (eg uncertain_conversion='inner' but better name than I can think of now) which would do your current behavior

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