Fix variant region for ins and dup on intron-exon boundary

src/hgvs/assemblymapper.py

@@ -4,6 +4,8 @@
 
 import logging
 
+from bioutils.sequences import reverse_complement
+
 import hgvs
 import hgvs.normalizer
 from hgvs.exceptions import (
@@ -241,6 +243,26 @@ def _alt_ac_for_tx_ac(self, tx_ac):
         assert len(alt_acs) == 1, "Should have exactly one alignment at this point"
         return alt_acs[0]
 
+    def _replace_reference(self, var):
+        if (getattr(var.posedit.pos.start, 'offset', 0) != 0 or getattr(var.posedit.pos.end, 'offset', 0) != 0):
+            if var.type != 'g':
+                alt_ac = self._alt_ac_for_tx_ac(var.ac)
+                if var.type == 'c':
+                    var_g = super(AssemblyMapper, self).c_to_g(var, alt_ac, alt_aln_method=self.alt_aln_method)
+                if var.type == 'n':
+                    var_g = super(AssemblyMapper, self).n_to_g(var, alt_ac, alt_aln_method=self.alt_aln_method)
+                if var.type == 't':
+                    var_g = super(AssemblyMapper, self).t_to_g(var, alt_ac, alt_aln_method=self.alt_aln_method)
+                super(AssemblyMapper, self)._replace_reference(var_g)
+                ref = var_g.posedit.edit.ref
+                if self._fetch_AlignmentMapper(tx_ac=var.ac).strand == -1:
+                    ref = reverse_complement(ref)
+                var.posedit.edit.ref = ref
+                _logger.debug("Replaced reference sequence in {var} with {ref}".format(var=var, ref=var_g.posedit.edit.ref))
+                return var
+
+        return super(AssemblyMapper, self)._replace_reference(var)
+
     def _fetch_AlignmentMapper(self, tx_ac, alt_ac=None, alt_aln_method=None):
         """convenience version of VariantMapper._fetch_AlignmentMapper that
         derives alt_ac from transcript, assembly, and alt_aln_method

src/hgvs/utils/altseqbuilder.py

@@ -11,6 +11,8 @@
 import logging
 import math
 
+from hgvs.exceptions import HGVSError
+
 import six
 from bioutils.sequences import reverse_complement, translate_cds
 
@@ -192,8 +194,17 @@ def _get_variant_region(self):
             and self._var_c.posedit.pos.end.datum == Datum.CDS_END
         ):
             result = self.WHOLE_GENE
+        elif self._var_c.posedit.edit.type == "ins" and self._var_c.posedit.pos.start.offset == -1 and self._var_c.posedit.pos.end.offset == 0:
+            # ins at intron-exon boundary
+            result = self.EXON
+        elif self._var_c.posedit.edit.type == "ins" and self._var_c.posedit.pos.start.offset == 0 and self._var_c.posedit.pos.end.offset == 1:
+            # ins at exon-intron boundary
+            result = self.EXON
+        elif self._var_c.posedit.edit.type == "dup" and self._var_c.posedit.pos.start.offset <= -1 and self._var_c.posedit.pos.end.offset >= -1:
+            # dup at intron-exon boundary
+            result = self.EXON
         elif self._var_c.posedit.pos.start.offset != 0 or self._var_c.posedit.pos.end.offset != 0:
-            # leave out anything intronic for now
+            # leave out anything else intronic for now
             result = self.INTRON
         else:  # anything else that contains an exon
             result = self.EXON
@@ -263,7 +274,10 @@ def _incorporate_dup(self):
         """Incorporate dup into sequence"""
         seq, cds_start, cds_stop, start, end = self._setup_incorporate()
 
-        dup_seq = seq[start:end]
+        if not self._var_c.posedit.edit.ref:
+            raise HGVSError('Duplication variant is missing reference sequence')
+
+        dup_seq = self._var_c.posedit.edit.ref
         seq[end:end] = dup_seq
 
         is_frameshift = len(dup_seq) % 3 != 0
@@ -326,7 +340,7 @@ def _setup_incorporate(self):
                     result = cds_start - 1
                 else:  # cds/intron
                     if pos.offset <= 0:
-                        result = (cds_start - 1) + pos.base - 1
+                        result = (cds_start - 1) + pos.base + pos.offset - 1
                     else:
                         result = (cds_start - 1) + pos.base
             elif pos.datum == Datum.CDS_END:  # 3' UTR

src/hgvs/variantmapper.py

@@ -433,6 +433,7 @@ def c_to_p(self, var_c, pro_ac=None):
             raise HGVSInvalidVariantError("Expected a cDNA (c.) variant; got " + str(var_c))
         if self._validator:
             self._validator.validate(var_c)
+        self._replace_reference(var_c)
         reference_data = RefTranscriptData(self.hdp, var_c.ac, pro_ac)
         builder = altseqbuilder.AltSeqBuilder(var_c, reference_data)
 
@@ -468,11 +469,10 @@ def _replace_reference(self, var):
             return var
 
         pos = var.posedit.pos
-        if (isinstance(pos.start, hgvs.location.BaseOffsetPosition) and pos.start.offset != 0) or (
-            isinstance(pos.end, hgvs.location.BaseOffsetPosition) and pos.end.offset != 0
-        ):
-            _logger.info("Can't update reference sequence for intronic variant {}".format(var))
-            return var
+        if (getattr(pos.start, 'offset', 0) != 0 or getattr(pos.end, 'offset', 0) != 0):
+            if var.type != "g":
+                _logger.info("Can't update reference sequence for intronic variant {}".format(var))
+                return var
 
         # For c. variants, we need coords on underlying sequences
         if var.type == "c":
@@ -483,8 +483,8 @@ def _replace_reference(self, var):
         else:
             pos = var.posedit.pos
 
-        seq_start = pos.start.base - 1
-        seq_end = pos.end.base
+        seq_start = pos.start.base + getattr(pos.start, 'offset', 0) - 1
+        seq_end = pos.end.base + getattr(pos.end, 'offset', 0)
 
         # When strict_bounds is False and an error occurs, return
         # variant as-is

tests/data/sanity_cp.tsv

@@ -1,10 +1,10 @@
-accession	transcript_sequence	cds_start_i	cds_end_i
-NM_999999.1	AAAATCAAAATGAAAGCGAAAGCGTTTCGCGCGAAATAGGGG	9	39
-NM_999998.1	AAAATCAAAATGAAAGCGAAAGCGTTTCGCGCGAAATAGAGGAGGTAGTTTCGC	9	39
-NM_999997.1	AAAATCAAAATGAAAGCGAAAGCGTTTCGCGTAGAATAGAGGAGGCAGTTTCGC	9	39
-NM_999996.1	AAAATCAAAATGAAATCGAAAGCGTTTCGCGCGAAATAGAGGAGGCAGTTTCGC	9	39
-NM_999995.1	AAAATCAAAATGAAAAAATCGAAAGCGTTTCGCGCGAAATAGAGGAGGCAGTTTCGC	9	42
-NM_999994.1	AAAATCAAAATGAAAAAAAAATCGAAAGCGTTTCGCGCGAAATAGAGGAGGCAGTTTCGC	9	45
-NM_999993.1	AAAATCAAAATGGGGAGGGCCCGGCAGCCAGCTTTATAGAGGAGGCAGTTTCGC	9	39
-NM_999992.1	AAAATCAAAATGGGGTAGGCCCGGCAGCCAGCTTTATAGAGGAGGCAGTTTCGC	9	39
-NM_999992.2	AAAATCAAAATGGGGTAGGCCCGGCAGCCAGCTTTATAGAGGAGGCAGTTTCGCC	9	40
+accession	transcript_sequence	cds_start_i	cds_end_i	lengths
+NM_999999.1	AAAATCAAAATGAAAGCGAAAGCGTTTCGCGCGAAATAGGGG	9	39	[10,25,30]
+NM_999998.1	AAAATCAAAATGAAAGCGAAAGCGTTTCGCGCGAAATAGAGGAGGTAGTTTCGC	9	39	[10,25,30]
+NM_999997.1	AAAATCAAAATGAAAGCGAAAGCGTTTCGCGTAGAATAGAGGAGGCAGTTTCGC	9	39	[10,25,30]
+NM_999996.1	AAAATCAAAATGAAATCGAAAGCGTTTCGCGCGAAATAGAGGAGGCAGTTTCGC	9	39	[10,25,30]
+NM_999995.1	AAAATCAAAATGAAAAAATCGAAAGCGTTTCGCGCGAAATAGAGGAGGCAGTTTCGC	9	42	[10,25,30]
+NM_999994.1	AAAATCAAAATGAAAAAAAAATCGAAAGCGTTTCGCGCGAAATAGAGGAGGCAGTTTCGC	9	45	[10,25,30]
+NM_999993.1	AAAATCAAAATGGGGAGGGCCCGGCAGCCAGCTTTATAGAGGAGGCAGTTTCGC	9	39	[10,25,30]
+NM_999992.1	AAAATCAAAATGGGGTAGGCCCGGCAGCCAGCTTTATAGAGGAGGCAGTTTCGC	9	39	[10,25,30]
+NM_999992.2	AAAATCAAAATGGGGTAGGCCCGGCAGCCAGCTTTATAGAGGAGGCAGTTTCGCC	9	40	[10,25,30]

tests/support/mock_input_source.py

@@ -33,7 +33,7 @@ def fetch_transcript_info(self, ac):
         result = None
         data = self._mock_data.get(ac)
         if data:  # interbase coordinates
-            result = {"cds_start_i": data["cds_start_i"], "cds_end_i": data["cds_end_i"]}
+            result = {"cds_start_i": data["cds_start_i"], "cds_end_i": data["cds_end_i"], "lengths": data["lengths"]}
         return result
 
     def get_tx_identity_info(self, ac):
@@ -74,6 +74,7 @@ def _read_input(self, in_file):
                     "transcript_sequence": row["transcript_sequence"],
                     "cds_start_i": int(row["cds_start_i"]),
                     "cds_end_i": int(row["cds_end_i"]),
+                    "lengths": eval(row["lengths"]),
                 }
 
         return result

tests/test_hgvs_assemblymapper.py

@@ -200,6 +200,57 @@ def test_c_to_p_with_stop_gain(self):
 
         self.assertEqual(str(var_p), hgvs_p)
 
+    def test_map_of_dup_intron_exon_boundary(self):
+        hgvs_c = "NM_004380.2:c.3251-1dup"
+        hgvs_p = "NP_004371.2:p.(Ile1084SerfsTer3)"
+
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.am.c_to_p(var_c)
+
+        self.assertEqual(str(var_p), hgvs_p)
+
+        hgvs_c = "NM_024529.4:c.132-2_132-1dup"
+        hgvs_p = "NP_078805.3:p.(Thr45GlyfsTer65)"
+
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.am.c_to_p(var_c)
+
+        self.assertEqual(str(var_p), hgvs_p)
+
+        hgvs_c = "NM_004985.4:c.112-1_113dup"
+        hgvs_p = "NP_004976.2:p.(Glu37dup)"
+
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.am.c_to_p(var_c)
+
+        self.assertEqual(str(var_p), hgvs_p)
+
+        hgvs_c = "NM_004380.2:c.3251dup"
+        hgvs_p = "NP_004371.2:p.(Phe1085LeufsTer2)"
+
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.am.c_to_p(var_c)
+
+        self.assertEqual(str(var_p), hgvs_p)
+
+    def test_map_of_dup_exon_intron_boundary(self):
+        hgvs_c = "NM_021140.3:c.619dup"
+        hgvs_p = "NP_066963.2:p.(Ile207AsnfsTer10)"
+
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.am.c_to_p(var_c)
+
+        self.assertEqual(str(var_p), hgvs_p)
+
+    def test_map_of_dup_intron_exon_boundary_rc(self):
+        hgvs_c = "NM_004985.4:c.112-1_112dup"
+        hgvs_p = "NP_004976.2:p.(Asp38GlyfsTer8)"
+
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.am.c_to_p(var_c)
+
+        self.assertEqual(str(var_p), hgvs_p)
+
 
 class Test_RefReplacement(unittest.TestCase):
     test_cases = [

tests/test_hgvs_variantmapper.py

@@ -118,6 +118,51 @@ def test_map_of_c_out_of_reference_bound(self):
         with pytest.raises(HGVSError, match="coordinate is out of bounds"):
             self.vm.c_to_p(var_c)
 
+    def test_map_of_ins_intron_exon_boundary(self):
+        hgvs_c = "NM_004380.2:c.3251-1_3251insA"
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.vm.c_to_p(var_c)
+        self.assertEqual(str(var_p), "NP_004371.2:p.(Ile1084AsnfsTer3)")
+
+    def test_map_of_ins_exon_intron_boundary(self):
+        hgvs_c = "NM_004380.2:c.3250_3250+1insT"
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.vm.c_to_p(var_c)
+        self.assertEqual(str(var_p), "NP_004371.2:p.(Phe1085LeufsTer2)")
+
+    def test_map_of_dup_intron_exon_boundary(self):
+        hgvs_c = "NM_004380.2:c.3251-1dup"
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        with self.assertRaises(HGVSError):
+            var_p = self.vm.c_to_p(var_c)
+
+        hgvs_c = "NM_024529.4:c.132-2_132-1dup"
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        with self.assertRaises(HGVSError):
+            var_p = self.vm.c_to_p(var_c)
+
+        hgvs_c = "NM_004985.4:c.112-1_113dup"
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        with self.assertRaises(HGVSError):
+            var_p = self.vm.c_to_p(var_c)
+
+        hgvs_c = "NM_004380.2:c.3251dup"
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.vm.c_to_p(var_c)
+        self.assertEqual(str(var_p), "NP_004371.2:p.(Phe1085LeufsTer2)")
+
+    def test_map_of_dup_exon_intron_boundary(self):
+        hgvs_c = "NM_021140.3:c.619dup"
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        var_p = self.vm.c_to_p(var_c)
+        self.assertEqual(str(var_p), "NP_066963.2:p.(Ile207AsnfsTer10)")
+
+    def test_map_of_dup_intron_exon_boundary_rc(self):
+        hgvs_c = "NM_004985.4:c.112-1_112dup"
+        var_c = self.hp.parse_hgvs_variant(hgvs_c)
+        with self.assertRaises(HGVSError):
+            var_p = self.vm.c_to_p(var_c)
+
 
 if __name__ == "__main__":
     unittest.main()

tests/test_hgvs_variantmapper_cp_altseqbuilder.py

@@ -118,6 +118,7 @@ def test_sequence_with_length_that_is_not_divisible_by_3(self):
     def _run_comparison(self, hgvsc, expected_sequence):
         ac_p = "DUMMY"
         var = self._parser.parse_hgvs_variant(hgvsc)
+        var.fill_ref(self._datasource)
         transcript_data = RefTranscriptData(hdp=self._datasource, tx_ac=var.ac, pro_ac=ac_p)
 
         builder = altseqbuilder.AltSeqBuilder(var, transcript_data)

tests/test_hgvs_variantmapper_cp_sanity.py

@@ -11,6 +11,7 @@
 
 import hgvs.parser
 import hgvs.variantmapper as variantmapper
+from hgvs.exceptions import HGVSError
 
 
 class TestHgvsCToP(unittest.TestCase):
@@ -154,6 +155,27 @@ def test_intron(self):
         hgvsp_expected = "MOCK:p.?"
         self._run_conversion(hgvsc, hgvsp_expected)
 
+    def test_ins_intron_exon_boundary(self):
+        hgvsc = "NM_999999.1:c.9-1_9insG"
+        hgvsp_expected = "MOCK:p.(Lys4GlufsTer?)"
+        self._run_conversion(hgvsc, hgvsp_expected)
+
+    def test_ins_exon_intron_boundary(self):
+        hgvsc = "NM_999999.1:c.39_39+1insC"
+        hgvsp_expected = "MOCK:p.(=)"
+        self._run_conversion(hgvsc, hgvsp_expected)
+
+    def test_dup_intron_exon_boundary(self):
+        hgvsc = "NM_999999.1:c.9-1dup"
+        hgvsp_expected = "MOCK:p.?"
+        with self.assertRaises(HGVSError):
+            self._run_conversion(hgvsc, hgvsp_expected)
+
+    def test_dup_exon_intron_boundary(self):
+        hgvsc = "NM_999999.1:c.39+1dup"
+        hgvsp_expected = "MOCK:p.?"
+        self._run_conversion(hgvsc, hgvsp_expected)
+
     def test_five_prime_utr(self):
         hgvsc = "NM_999999.1:c.-2A>G"
         hgvsp_expected = "MOCK:p.?"