Closes #557: Add option to format translation initiation codon varian…

…ts as `p.Met1?`

p.Met1? is the new default

hgvs/_data/defaults.ini

@@ -11,6 +11,7 @@ replace_reference = True
 max_ref_length = 0
 p_3_letter = True
 p_term_asterisk = False
+p_init_met = True
 
 [validator]
 strict = True

hgvs/edit.py

@@ -34,11 +34,15 @@ def _format_config_na(self, conf=None):
     def _format_config_aa(self, conf=None):
         p_3_letter = hgvs.global_config.formatting.p_3_letter
         p_term_asterisk = hgvs.global_config.formatting.p_term_asterisk
+        p_init_met = hgvs.global_config.formatting.p_init_met
+
         if conf and "p_3_letter" in conf and conf["p_3_letter"] is not None:
             p_3_letter = conf["p_3_letter"]
         if conf and "p_term_asterisk" in conf and conf["p_term_asterisk"] is not None:
             p_term_asterisk = conf["p_term_asterisk"]
-        return p_3_letter, p_term_asterisk
+        if conf and "p_init_met" in conf and conf["p_init_met"] is not None:
+            p_init_met = conf["p_init_met"]
+        return p_3_letter, p_term_asterisk, p_init_met
 
     def _del_ins_lengths(self, ilen):
         raise HGVSUnsupportedOperationError(
@@ -169,6 +173,7 @@ class AARefAlt(Edit):
     ref = attr.ib(default=None)
     alt = attr.ib(default=None)
     uncertain = attr.ib(default=False)
+    init_met = attr.ib(default=False)
 
     def __attrs_post_init__(self):
         self.ref = aa_to_aa1(self.ref)
@@ -179,10 +184,14 @@ def format(self, conf=None):
             # raise HGVSError("RefAlt: ref and alt sequences are both undefined")
             return "="
 
-        p_3_letter, p_term_asterisk = self._format_config_aa(conf)
+        p_3_letter, p_term_asterisk, p_init_met = self._format_config_aa(conf)
 
+        if self.init_met and p_init_met:
+            s = "Met1?"
+        elif self.init_met and not p_init_met:
+            s = "?"
         # subst and delins
-        if self.ref is not None and self.alt is not None:
+        elif self.ref is not None and self.alt is not None:
             if self.ref == self.alt:
                 if p_3_letter:
                     s = "{ref}=".format(ref=aa1_to_aa3(self.ref))
@@ -267,7 +276,7 @@ def _del_ins_lengths(self, ilen):
 @attr.s(slots=True)
 class AASub(AARefAlt):
     def format(self, conf=None):
-        p_3_letter, p_term_asterisk = self._format_config_aa(conf)
+        p_3_letter, p_term_asterisk, p_init_met = self._format_config_aa(conf)
 
         if p_3_letter:
             s = aa1_to_aa3(self.alt) if self.alt != "?" else self.alt
@@ -300,7 +309,7 @@ def __attrs_post_init__(self):
         self.alt = aa_to_aa1(self.alt)
 
     def format(self, conf=None):
-        p_3_letter, p_term_asterisk = self._format_config_aa(conf)
+        p_3_letter, p_term_asterisk, p_init_met = self._format_config_aa(conf)
 
         st_length = self.length or ""
         if p_3_letter:
@@ -345,7 +354,7 @@ def __attrs_post_init__(self):
         self.aaterm = aa_to_aa1(self.aaterm)
 
     def format(self, conf=None):
-        p_3_letter, p_term_asterisk = self._format_config_aa(conf)
+        p_3_letter, p_term_asterisk, p_init_met = self._format_config_aa(conf)
 
         st_alt = self.alt or ""
         st_aaterm = self.aaterm or ""

hgvs/normalizer.py

@@ -5,7 +5,6 @@
 from __future__ import absolute_import, division, print_function, unicode_literals
 
 import copy
-import logging
 
 from bioutils.sequences import reverse_complement
 
@@ -14,7 +13,6 @@
 import hgvs.variantmapper
 from hgvs.utils.norm import normalize_alleles
 from hgvs.exceptions import HGVSDataNotAvailableError, HGVSUnsupportedOperationError, HGVSInvalidVariantError
-from six.moves import range
 
 
 class Normalizer(object):
@@ -57,7 +55,11 @@ def normalize(self, var):
         if self.validator:
             self.validator.validate(var)
 
-        if var.posedit is None or var.posedit.uncertain or var.posedit.pos is None:
+        init_met = False
+        if var.posedit is not None and isinstance(var.posedit, hgvs.edit.AARefAlt):
+            init_met = var.posedit.init_met
+
+        if var.posedit is None or var.posedit.uncertain or init_met or var.posedit.pos is None:
             return var
 
         type = var.type

hgvs/utils/altseq_to_hgvsp.py

@@ -35,6 +35,7 @@ def __init__(self, ref_data, alt_data):
         self._frameshift_start = self._alt_data.frameshift_start
         self._is_substitution = self._alt_data.is_substitution
         self._is_ambiguous = self._alt_data.is_ambiguous
+        self._is_init_met = False
 
         if DBG:
             print("len ref seq:{} len alt seq:{}".format(len(self._ref_seq), len(self._alt_seq)))
@@ -186,6 +187,7 @@ def _convert_to_sequence_variants(self, variant, acc):
             aa_start = aa_end = AAPosition(base=start, aa=deletion)
             ref = ''
             alt = ''
+            self._is_init_met = True
             self._is_ambiguous = True    # side-effect
 
         if insertion and insertion.find("*") == 0:    # stop codon at variant position
@@ -288,7 +290,9 @@ def _convert_to_sequence_variants(self, variant, acc):
             acc=acc,
             is_ambiguous=self._is_ambiguous,
             is_sub=is_sub,
-            is_ext=is_ext)
+            is_ext=is_ext,
+            is_init_met=self._is_init_met
+        )
 
         return var_p
 
@@ -324,9 +328,13 @@ def _create_variant(self,
                         is_ambiguous=False,
                         is_sub=False,
                         is_ext=False,
-                        is_no_protein=False):
+                        is_no_protein=False,
+                        is_init_met=False):
         """Creates a SequenceVariant object"""
-        if is_ambiguous:
+
+        if is_init_met:
+            posedit = AARefAlt(ref=ref, alt=alt, init_met=True)
+        elif is_ambiguous:
             posedit = None
         else:
             interval = Interval(start=start, end=end)

tests/data/ext.tsv

@@ -8,3 +8,7 @@ EXT06		NM_152263.2:c.855delA	NP_689476.2:p.(Ter286Asnext*73)
 MULTISTOP01	NC_000001.10:g.26136244G>A	NM_020451.2:c.943G>A	NP_065184.2:p.?
 WHOLEGENE01		NM_000249.3:c.-7_*46del	NP_000240.1:p.0?
 WHOLEGENE02	NC_000003.11:g.37035019_37092164del	NM_000249.3:c.-20_*20del	NP_000240.1:p.0?
+INITMET01	NC_000012.11:g.66583080A>G	NM_007199.2:c.1A>G	NP_009130.2:p.Met1?
+INITMET02	NC_000001.10:g.231557634_231557635insGGC	NM_022051.2:c.-1_1insGCC	NP_071334.1:p.Met1?
+INITMET03	NC_000016.9:g.89985654_89985683del	NM_002386.3:c.-11_19del	NP_002377.4:p.Met1?
+

tests/data/gcp/real.tsv

@@ -59,5 +59,5 @@ ID00057	NC_000010.10:g.89711873A>C	NM_000314.4:c.493-2A>C	NP_000305.3:p.?
 ID00058	NC_000010.10:g.89717676G>A	NM_000314.4:c.701G>A	NP_000305.3:p.(Arg234Gln)
 ID00059	NC_000010.10:g.89717777G>A	NM_000314.4:c.801+1G>A	NP_000305.3:p.?
 ID00060	NC_000010.10:g.89720648dupT	NM_000314.4:c.802-3dupT	NP_000305.3:p.?
-ID00061	NC_000005.9:g.131705667G>T	NM_003060.3:c.3G>T	NP_003051.1:p.?
+ID00061	NC_000005.9:g.131705667G>T	NM_003060.3:c.3G>T	NP_003051.1:p.Met1?
 ID00062	NC_000005.9:g.131706014G>A	NM_003060.3:c.350G>A	NP_003051.1:p.(Trp117*)

tests/test_hgvs_variantmapper_cp_real.py

@@ -26,12 +26,11 @@ def gcp_file_reader(fn):
             continue
         yield rec
 
-
 class TestHgvsCToPReal(unittest.TestCase):
     @classmethod
     def setUpClass(cls):
         cls.hdp = hgvs.dataproviders.uta.connect(
-            mode=os.environ.get("HGVS_CACHE_MODE", "run"), cache=CACHE)
+            mode=os.environ.get("HGVS_CACHE_MODE", "learn"), cache=CACHE)
         cls._hm = hgvs.variantmapper.VariantMapper(cls.hdp)
         cls._hp = hgvs.parser.Parser()
         cls._failed = []
@@ -86,6 +85,21 @@ def _append_fail(self, out, row_id, hgvsg, hgvsc, hgvsp_expected, hgvsp_actual,
         out.write("{}\t{}\t{}\t{}\t{}\t{}\n".format(row_id, hgvsg, hgvsc, hgvsp_expected,
                                                     hgvsp_actual, msg))
 
+    def test_c_to_p_format(self):
+        hgvsc = 'NM_022464.4:c.3G>A'
+        hgvsp_expected = 'NP_071909.1:p.Met1?'
+        hgvsp_expected_alternative = 'NP_071909.1:p.?'
+
+        var_c = self._hp.parse_hgvs_variant(hgvsc)
+        var_p = self._hm.c_to_p(
+            var_c, hgvsp_expected.split(":")[0])
+
+        default_format_p = var_p.format()
+        self.assertEqual(hgvsp_expected, default_format_p)
+
+        alt_format_p = var_p.format(conf={'p_init_met': False})
+        self.assertEqual(hgvsp_expected_alternative, alt_format_p)
+
 
 if __name__ == "__main__":
     unittest.main()

tests/test_hgvs_variantmapper_cp_sanity.py

@@ -184,22 +184,22 @@ def test_delins_into_three_prime_utr_no_frameshift(self):
     # http://varnomen.hgvs.org/recommendations/protein/variant/substitution/
     def test_substitution_removes_start_codon(self):
         hgvsc = "NM_999999.1:c.1A>G"
-        hgvsp_expected = "MOCK:p.?"
+        hgvsp_expected = "MOCK:p.Met1?"
         self._run_conversion(hgvsc, hgvsp_expected)
 
     def test_deletion_from_five_prime_utr_frameshift(self):
         hgvsc = "NM_999999.1:c.-3_1del"
-        hgvsp_expected = "MOCK:p.?"
+        hgvsp_expected = "MOCK:p.Met1?"
         self._run_conversion(hgvsc, hgvsp_expected)
 
     def test_deletion_from_five_prime_utr_no_frameshift(self):
         hgvsc = "NM_999999.1:c.-3_3del"
-        hgvsp_expected = "MOCK:p.?"
+        hgvsp_expected = "MOCK:p.Met1?"
         self._run_conversion(hgvsc, hgvsp_expected)
 
     def test_delins_from_five_prime_utr_no_frameshift(self):
         hgvsc = "NM_999999.1:c.-3_3delinsAAA"
-        hgvsp_expected = "MOCK:p.?"
+        hgvsp_expected = "MOCK:p.Met1?"
         self._run_conversion(hgvsc, hgvsp_expected)
 
     def test_delete_entire_gene(self):