Update to issues #501 & #473 - Include VariantEffect and geneSymbol a…

…nnotations on ClinVarData at build time.

exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDao.java

@@ -1,19 +1,20 @@
 package org.monarchinitiative.exomiser.core.genome.dao;
 
-import org.monarchinitiative.exomiser.core.model.Variant;
 import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData;
+import org.monarchinitiative.svart.GenomicInterval;
+import org.monarchinitiative.svart.GenomicVariant;
+
+import java.util.Map;
 
 
 /**
- * Interface for providing {@link ClinVarData} about a {@link Variant}.
+ * Interface for providing {@link ClinVarData} about a {@link GenomicVariant}.
  *
  * @since 14.0.0
  */
 public interface ClinVarDao {
 
-    ClinVarData getClinVarData(Variant variant);
-
-//    List<ClinVarData> findClinVarRecordsOverlappingRegion(GenomicInterval genomicInterval);
-    ////            Map<AlleleKey, PathogenicityData> pathogenicityData = mvStoreDao.getPathogenicityDataForRange(chr, min, max);
+    ClinVarData getClinVarData(GenomicVariant variant);
 
+    Map<GenomicVariant, ClinVarData> findClinVarRecordsOverlappingInterval(GenomicInterval genomicInterval);
 }

exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStore.java

@@ -4,13 +4,16 @@
 import org.h2.mvstore.MVStore;
 import org.monarchinitiative.exomiser.core.genome.dao.serialisers.MvStoreUtil;
 import org.monarchinitiative.exomiser.core.model.AlleleProtoAdaptor;
-import org.monarchinitiative.exomiser.core.model.Variant;
 import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData;
 import org.monarchinitiative.exomiser.core.proto.AlleleProto;
+import org.monarchinitiative.svart.*;
 import org.slf4j.Logger;
 import org.slf4j.LoggerFactory;
 
 import javax.annotation.Nonnull;
+import java.util.Iterator;
+import java.util.LinkedHashMap;
+import java.util.Map;
 
 /**
  * @since 14.0.0
@@ -26,9 +29,60 @@ public ClinVarDaoMvStore(MVStore mvStore) {
     }
 
     @Override
-    public ClinVarData getClinVarData(@Nonnull Variant variant) {
+    public ClinVarData getClinVarData(@Nonnull GenomicVariant variant) {
         AlleleProto.AlleleKey alleleKey = AlleleProtoAdaptor.toAlleleKey(variant);
+        return getClinVarData(alleleKey);
+    }
+
+    private ClinVarData getClinVarData(AlleleProto.AlleleKey alleleKey) {
         AlleleProto.ClinVar clinVar = clinVarMap.get(alleleKey);
         return clinVar == null ? ClinVarData.empty() : AlleleProtoAdaptor.toClinVarData(clinVar);
     }
+
+    @Override
+    public Map<GenomicVariant, ClinVarData> findClinVarRecordsOverlappingInterval(GenomicInterval genomicInterval) {
+        Contig contig = genomicInterval.contig();
+
+        int chr = genomicInterval.contigId();
+        int start = genomicInterval.start();
+        int end = genomicInterval.end();
+
+        // build Allele keys for map and define bounds
+        AlleleProto.AlleleKey lowerBound = AlleleProto.AlleleKey.newBuilder()
+                .setChr(chr)
+                .setPosition(start)
+                .build();
+        AlleleProto.AlleleKey upperBound = AlleleProto.AlleleKey.newBuilder()
+                .setChr(chr)
+                .setPosition(end)
+                .build();
+
+        AlleleProto.AlleleKey floorKey = clinVarMap.floorKey(lowerBound);
+        if (floorKey != null && floorKey.getPosition() < lowerBound.getPosition()) {
+            lowerBound = floorKey;
+        }
+
+        Map<GenomicVariant, ClinVarData> results = new LinkedHashMap<>();
+
+        Iterator<AlleleProto.AlleleKey> keyIterator = clinVarMap.keyIterator(lowerBound);
+        while (keyIterator.hasNext()) {
+            AlleleProto.AlleleKey ak = keyIterator.next();
+            // don't process keys out of the initial boundaries
+            if (ak.getPosition() >= start && ak.getPosition() <= end) {
+                GenomicVariant gvFromAk = alleleKeyToGenomicVariant(ak, contig, genomicInterval.coordinateSystem());
+                ClinVarData cvData = getClinVarData(ak);
+                results.put(gvFromAk, cvData);
+            }
+            if (ak.getPosition() > upperBound.getPosition()) {
+                break;
+            }
+        }
+        return results;
+    }
+
+    private GenomicVariant alleleKeyToGenomicVariant(AlleleProto.AlleleKey alleleKey, Contig contig, CoordinateSystem coordinateSystem) {
+        return GenomicVariant.builder()
+                .variant(contig, Strand.POSITIVE, Coordinates.ofAllele(coordinateSystem, alleleKey.getPosition(), alleleKey.getRef()), alleleKey.getRef(), alleleKey.getAlt()).build();
+    }
+
 }

exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStoreTest.java

@@ -1,28 +1,80 @@
 package org.monarchinitiative.exomiser.core.genome.dao;
 
+import org.h2.mvstore.MVMap;
 import org.h2.mvstore.MVStore;
 import org.junit.jupiter.api.Test;
 import org.monarchinitiative.exomiser.core.genome.GenomeAssembly;
 import org.monarchinitiative.exomiser.core.genome.dao.serialisers.MvStoreUtil;
 import org.monarchinitiative.exomiser.core.model.AlleleProtoAdaptor;
-import org.monarchinitiative.exomiser.core.model.Variant;
-import org.monarchinitiative.exomiser.core.model.VariantEvaluation;
 import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData;
 import org.monarchinitiative.exomiser.core.proto.AlleleProto;
+import org.monarchinitiative.svart.CoordinateSystem;
 import org.monarchinitiative.svart.Coordinates;
 import org.monarchinitiative.svart.GenomicVariant;
 import org.monarchinitiative.svart.Strand;
 
+import java.util.Set;
+
 import static org.hamcrest.MatcherAssert.assertThat;
 import static org.hamcrest.Matchers.equalTo;
 
 class ClinVarDaoMvStoreTest {
 
+    private ClinVarDaoMvStore buildClinVarDaoMvStore(String... broadFormatVariants) {
+        // open an in-memory store
+        MVStore mvStore = new MVStore.Builder().open();
+        MVMap<AlleleProto.AlleleKey, AlleleProto.ClinVar> clinVarMap = MvStoreUtil.openClinVarMVMap(mvStore);
+        for (String variant : broadFormatVariants) {
+            clinVarMap.put(parseAlleleKey(variant), AlleleProto.ClinVar.newBuilder().build());
+        }
+        return new ClinVarDaoMvStore(mvStore);
+    }
+
+    private AlleleProto.AlleleKey parseAlleleKey(String broadFormatVariant) {
+        String[] fields = broadFormatVariant.split("-");
+        return AlleleProto.AlleleKey.newBuilder()
+                .setChr(Integer.parseInt(fields[0]))
+                .setPosition(Integer.parseInt(fields[1]))
+                .setRef(fields[2])
+                .setAlt(fields[3])
+                .build();
+    }
+
+    private GenomicVariant parseVariant(String broadFormatVariant) {
+        String[] fields = broadFormatVariant.split("-");
+        return GenomicVariant.of(GenomeAssembly.HG19.getContigById(Integer.parseInt(fields[0])), Strand.POSITIVE, Coordinates.ofAllele(CoordinateSystem.ONE_BASED, Integer.parseInt(fields[1]), fields[2]), fields[2], fields[3]);
+    }
+
+    private final AlleleProto.AlleleKey positionStartMinus1 = parseAlleleKey("1-1229-A-G");
+    private final AlleleProto.AlleleKey positionEndPlus1 = parseAlleleKey("1-1231-C-G");
+
+    // Variants directly at the boundaries:
+    private final AlleleProto.AlleleKey positionStartMinus2 = parseAlleleKey("1-1228-A-G");
+    private final AlleleProto.AlleleKey positionEndPlus2 = parseAlleleKey("1-1232-T-A");
+
+    // Variants just outside the boundaries:
+    private final AlleleProto.AlleleKey positionStartMinus3 = parseAlleleKey("1-1227-A-G");
+    private final AlleleProto.AlleleKey positionEndPlus3 = parseAlleleKey("1-1233-C-T");
+
+    // Variants are exactly matching on position:
+    private final AlleleProto.AlleleKey positionExactlyMatches = parseAlleleKey("1-1230-T-G");
+
+    // Variants are exactly matching on position + but ref and alt are different
+    private final AlleleProto.AlleleKey positionExactlyMatchesButDifferentRefAlt = parseAlleleKey("1-1230-T-C");
+
+    // Variants are far out of boundaries:
+    private final AlleleProto.AlleleKey positionFarOutOfBoundariesMinus = parseAlleleKey("1-7700-A-G");
+    private final AlleleProto.AlleleKey positionFarOutOfBoundariesPlus = parseAlleleKey("1-1-A-G");
+
+    // two variants that are in range but Alt.length and Ref.length > 1
+    private final AlleleProto.AlleleKey positionInButLengthIncorrect = parseAlleleKey("1-1229-AA-G");
+    private final AlleleProto.AlleleKey positionInButLengthIncorrect1 = parseAlleleKey("1-1231-A-GG");
+
     @Test
     void getClinVarData() {
         try (MVStore mvStore = new MVStore.Builder().open()) {
             var clinvarMap = MvStoreUtil.openClinVarMVMap(mvStore);
-            AlleleProto.AlleleKey alleleKey = AlleleProto.AlleleKey.newBuilder().setChr(1).setPosition(200).setRef("A").setAlt("T").build();
+            AlleleProto.AlleleKey alleleKey = parseAlleleKey("1-200-A-T");
             AlleleProto.ClinVar clinVar = AlleleProto.ClinVar.newBuilder()
                     .setAlleleId("12345")
                     .setPrimaryInterpretation(AlleleProto.ClinVar.ClinSig.PATHOGENIC)
@@ -31,17 +83,104 @@ void getClinVarData() {
             clinvarMap.put(alleleKey, clinVar);
 
             ClinVarDao instance = new ClinVarDaoMvStore(mvStore);
-            Variant clinVarVariant = VariantEvaluation.builder()
-                    .variant(GenomeAssembly.HG19.getContigById(1), Strand.POSITIVE, Coordinates.oneBased(200, 200), "A", "T")
-                    .build();
 
+            GenomicVariant clinVarVariant = parseVariant("1-200-A-T");
             assertThat(instance.getClinVarData(clinVarVariant), equalTo(AlleleProtoAdaptor.toClinVarData(clinVar)));
 
-            Variant nonClinVarVariant = VariantEvaluation.builder()
-                    .variant(GenomeAssembly.HG19.getContigById(1), Strand.POSITIVE, Coordinates.oneBased(200, 200), "A", "A")
-                    .build();
-
+            GenomicVariant nonClinVarVariant = parseVariant("1-200-A-A");
             assertThat(instance.getClinVarData(nonClinVarVariant), equalTo(ClinVarData.empty()));
         }
     }
+
+    @Test
+    public void FiveInsideAndFourOutsideBoundaries() {
+        ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore(
+                "1-1-A-G",
+                "1-1227-A-G", // -3
+                "1-1228-A-G", // -2
+                "1-1229-A-G", // -1
+                "1-1230-T-G", // 0 same ref
+                "1-1230-T-C", // 0 same ref
+                "1-1231-C-G", // +1
+                "1-1232-T-A", // +2
+                "1-1233-C-T", // +3
+                "1-7700-A-G"
+                );
+
+        GenomicVariant genomicVariant = parseVariant("1-1230-T-A");
+
+        var result = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant.withPadding(2, 2));
+        assertThat(result.size(), equalTo(6));
+    }
+
+    @Test
+    public void variantsNonOverlap() {
+        ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore("1-1227-A-G", "1-1233-C-T");
+        GenomicVariant genomicVariant = parseVariant("1-1230-T-A");
+
+        var result = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant.withPadding(2, 2));
+        assertThat(result.size(), equalTo(0));
+
+    }
+
+    @Test
+    public void variantsOverlapDirectlyAtBoundaries() {
+        ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore("1-1228-A-G", "1-1232-T-A");
+        GenomicVariant genomicVariant = parseVariant("1-1230-T-A");
+
+        var result = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant.withPadding(2, 2));
+        assertThat(result.size(), equalTo(2));
+    }
+
+    @Test
+    public void variantsOverlapInsideBoundaries() {
+//        MVStore mvStore = newMvStore();
+//        MVMap<AlleleProto.AlleleKey, AlleleProto.ClinVar> clinVarMap = MvStoreUtil.openClinVarMVMap(mvStore);
+//        clinVarMap.put(parseAlleleKey("1-1229-A-G"), AlleleProto.ClinVar.newBuilder().build());
+//        clinVarMap.put(parseAlleleKey("1-1231-C-G"), AlleleProto.ClinVar.newBuilder().build());
+//        ClinVarDaoMvStore clinVarDao = new ClinVarDaoMvStore(mvStore);
+        ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore("1-1229-A-G", "1-1231-C-G");
+        GenomicVariant genomicVariant = parseVariant("1-1230-T-A");
+
+        var result = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant.withPadding(2, 2));
+        assertThat(result.size(), equalTo(2));
+    }
+
+    @Test
+    public void variantsExactlyMatchOnPosition() {
+        ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore("1-1230-T-G");
+        GenomicVariant genomicVariant = parseVariant("1-1230-T-A");
+
+        var result = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant);
+        assertThat(result.keySet(), equalTo(Set.of(parseVariant("1-1230-T-G"))));
+    }
+
+    @Test
+    public void variantsAreFarOutOfBoundaries() {
+        ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore("1-7700-A-G", "1-1-A-G");
+        GenomicVariant genomicVariant = parseVariant("1-1230-T-A");
+
+        var result = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant.withPadding(2, 2));
+        assertThat(result.size(), equalTo(0));
+
+    }
+
+    @Test
+    public void noVariantsGettingAddedNoOverlap() {
+        ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore();
+        GenomicVariant genomicVariant = parseVariant("1-1230-T-A");
+
+        var result = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant.withPadding(2, 2));
+        assertThat(result.size(), equalTo(0));
+
+    }
+
+    @Test
+    public void setPositionInButLengthIncorrectTest() {
+        ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore("1-1228-AA-G", "1-1231-A-GG");
+        GenomicVariant genomicVariant = parseVariant("1-1230-T-A");
+
+        var result = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant.withPadding(2, 2));
+        assertThat(result.size(), equalTo(2));
+    }
 }

exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/ClinVarBuildRunner.java

@@ -9,6 +9,7 @@
 import org.monarchinitiative.exomiser.core.genome.VariantAnnotator;
 import org.monarchinitiative.exomiser.core.genome.dao.serialisers.MvStoreUtil;
 import org.monarchinitiative.exomiser.core.model.ChromosomalRegionIndex;
+import org.monarchinitiative.exomiser.core.model.TranscriptAnnotation;
 import org.monarchinitiative.exomiser.core.model.VariantAnnotation;
 import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData;
 import org.monarchinitiative.exomiser.core.proto.AlleleProto;
@@ -90,10 +91,13 @@ private ClinVarData annotateClinvar(Allele allele) {
         List<VariantAnnotation> variantAnnotations = variantAnnotator.annotate(genomicVariant);
         if (!variantAnnotations.isEmpty()) {
             VariantAnnotation variantAnnotation = variantAnnotations.get(0);
+            TranscriptAnnotation transcriptAnnotation = variantAnnotation.getTranscriptAnnotations().get(0);
             return allele.getClinVarData()
                     .toBuilder()
                     .geneSymbol(variantAnnotation.getGeneSymbol())
                     .variantEffect(variantAnnotation.getVariantEffect())
+//                builder.hgvsCdna(transcriptAnnotation == null ? "" : transcriptAnnotation.getHgvsCdna());  // TODO need cDNA info for PS1/PM5
+//                builder.hgvsProtein(transcriptAnnotation == null ? "" : transcriptAnnotation.getHgvsProtein()); // TODO need AA info for PS1/PM5
                     .build();
         }
         return allele.getClinVarData();