syntax = "proto3";

package varfish.v1.seqvars.query;

// Enumeration for recessive mode queries.
enum RecessiveMode {
  // Unknown recessive mode.
  RECESSIVE_MODE_UNSPECIFIED = 0;
  // Disabled recessive mode.
  RECESSIVE_MODE_DISABLED = 1;
  // Compound heterozygous recessive mode.
  RECESSIVE_MODE_COMPOUND_HETEROZYGOUS = 2;
  // Homozygous recessive mode.
  RECESSIVE_MODE_HOMOZYGOUS = 3;
  // Generic recessive mode.
  RECESSIVE_MODE_ANY = 4;
}

// Choice for genotype.
enum GenotypeChoice {
  // Unknown genotype.
  GENOTYPE_CHOICE_UNSPECIFIED = 0;
  // Any genoype.
  GENOTYPE_CHOICE_ANY = 1;
  // Reference genotype.
  GENOTYPE_CHOICE_REF = 2;
  // Heterozygous genotype.
  GENOTYPE_CHOICE_HET = 3;
  // Homozygous genotype.
  GENOTYPE_CHOICE_HOM = 4;
  // Non-heterozygous genotype.
  GENOTYPE_CHOICE_NON_HET = 5;
  // Non-homozygous genotype.
  GENOTYPE_CHOICE_NON_HOM = 6;
  // Variant genotype.
  GENOTYPE_CHOICE_VARIANT = 7;
  // Recessive index.
  GENOTYPE_CHOICE_RECESSIVE_INDEX = 8;
  // Recessive father.
  GENOTYPE_CHOICE_RECESSIVE_FATHER = 9;
  // Recessive mother.
  GENOTYPE_CHOICE_RECESSIVE_MOTHER = 10;
}

// Genotype choice for one sample.
message SampleGenotypeChoice {
  // Name of the sample filtered for
  string sample = 1;
  // Genotype choice
  GenotypeChoice genotype = 2;
  // Whether to include no-call (will disable quality filter).
  bool include_no_call = 3;
  // Whether to enable sample in filtration
  bool enabled = 4;
}

// Genotype-related filter settings.
message QuerySettingsGenotype {
  // Recessive mode
  RecessiveMode recessive_mode = 1;
  // List of sample genotype choices
  repeated SampleGenotypeChoice sample_genotypes = 2;
}

// Quality settings for one sample.
message SampleQualitySettings {
  // Name of the sample filtered for
  string sample = 1;
  // Drop whole variant on failure
  bool filter_active = 2;
  // Minimal coverage for het. sites
  optional int32 min_dp_het = 3;
  // Minimal coverage for hom. sites
  optional int32 min_dp_hom = 4;
  // Minimal genotype quality
  optional int32 min_gq = 5;
  // Minimal allele balance for het. variants
  optional float min_ab = 6;
  // Minimal number of alternate reads
  optional int32 min_ad = 7;
  // Maximal number of alternate reads
  optional int32 max_ad = 8;
}

// Per-sample quality filter settings.
message QuerySettingsQuality {
  // List of sample quality settings
  repeated SampleQualitySettings sample_qualities = 1;
}

// gnomAD filter options.
message NuclearFrequencySettings {
  // Whether to enable filtration.
  bool enabled = 1;
  // Maximal number of heterozygous carriers
  optional int32 max_het = 2;
  // Maximal number of homozygous carriers
  optional int32 max_hom = 3;
  // Maximal number of hemizygous carriers
  optional int32 max_hemi = 4;
  // Maximal allele frequency.
  optional float max_af = 5;
}

// Mitochondrial filter options.
message MitochondrialFrequencySettings {
  // Whether to enable filtration.
  bool enabled = 1;
  // Maximal number of heteroplasmic carriers.
  optional int32 max_het = 2;
  // Maximal number of homoplasmic carriers.
  optional int32 max_hom = 3;
  // Maximal allele frequency.
  optional float max_af = 4;
}

// In-house filter options.
message InhouseFrequencySettings {
  // Whether to enable filtration.
  bool enabled = 1;
  // Maximal number of heterozygous carriers
  optional int32 max_het = 2;
  // Maximal number of homozygous carriers
  optional int32 max_hom = 3;
  // Maximal number of hemizygous carriers
  optional int32 max_hemi = 4;
  // Maximal number of total carriers.
  optional int32 max_carriers = 5;
}

// Population frequency filter options.
message QuerySettingsFrequency {
  // gnomAD-exomes filter
  NuclearFrequencySettings gnomad_exomes = 1;
  // gnomAD-genomes filter
  NuclearFrequencySettings gnomad_genomes = 2;
  // gnomAD-MT filter
  MitochondrialFrequencySettings gnomad_mtdna = 3;
  // HelixMtDb filter
  MitochondrialFrequencySettings helixmtdb = 4;
  // In-house filter
  InhouseFrequencySettings inhouse = 5;
}

// The variant types.
enum VariantType {
  // Unknown variant type
  VARIANT_TYPE_UNSPECIFIED = 0;
  // SNV
  VARIANT_TYPE_SNV = 1;
  // Indel
  VARIANT_TYPE_INDEL = 2;
  // MNV
  VARIANT_TYPE_MNV = 3;
  // Complex Substitution
  VARIANT_TYPE_COMPLEX_SUBSTITUTION = 4;
}

// Transcript types to consider.
enum TranscriptType {
  // Unknown transcript type.
  TRANSCRIPT_TYPE_UNSPECIFIED = 0;
  // Coding transcript.
  TRANSCRIPT_TYPE_CODING = 1;
  // Non-coding transcript.
  TRANSCRIPT_TYPE_NON_CODING = 2;
}

// The Variant consequence
enum Consequence {
  // Unknown consequence.
  CONSEQUENCE_UNSPECIFIED = 0;
  /*
   * high impact
   */
  // Transcript ablation.
  CONSEQUENCE_TRANSCRIPT_ABLATION = 1;
  // Exon loss variant.
  CONSEQUENCE_EXON_LOSS_VARIANT = 2;
  // Splice acceptor variant
  CONSEQUENCE_SPLICE_ACCEPTOR_VARIANT = 3;
  // Splice donor variant
  CONSEQUENCE_SPLICE_DONOR_VARIANT = 4;
  // Stop gained
  CONSEQUENCE_STOP_GAINED = 5;
  // Frameshift variant
  CONSEQUENCE_FRAMESHIFT_VARIANT = 6;
  // Stop lost
  CONSEQUENCE_STOP_LOST = 7;
  // Start lost
  CONSEQUENCE_START_LOST = 8;
  // Transcript amplification
  CONSEQUENCE_TRANSCRIPT_AMPLIFICATION = 9;
  // Feature elongation.
  CONSEQUENCE_FEATURE_ELONGATION = 10;
  // Feature truncation.
  CONSEQUENCE_FEATURE_TRUNCATION = 11;
  /*
   * moderate impact
   */
  // Disruptive inframe insertion
  CONSEQUENCE_DISRUPTIVE_INFRAME_INSERTION = 12;
  // Disruptive inframe deletion
  CONSEQUENCE_DISRUPTIVE_INFRAME_DELETION = 13;
  // Conservative inframe insertion
  CONSEQUENCE_CONSERVATIVE_INFRAME_INSERTION = 14;
  // Conservative inframe deletion
  CONSEQUENCE_CONSERVATIVE_INFRAME_DELETION = 15;
  // Missense variant
  CONSEQUENCE_MISSENSE_VARIANT = 16;
  /*
   * low impact
   */
  // Splice donor 5th base variant.
  CONSEQUENCE_SPLICE_DONOR_FIFTH_BASE_VARIANT = 17;
  // Splice region variant.
  CONSEQUENCE_SPLICE_REGION_VARIANT = 18;
  // Splice donor region variant.
  CONSEQUENCE_SPLICE_DONOR_REGION_VARIANT = 19;
  // Splice polypyrimidine tract variant.
  CONSEQUENCE_SPLICE_POLYPYRIMIDINE_TRACT_VARIANT = 20;
  // Start retained variant.
  CONSEQUENCE_START_RETAINED_VARIANT = 21;
  // Stop retained variant.
  CONSEQUENCE_STOP_RETAINED_VARIANT = 22;
  // Synonymous variant.
  CONSEQUENCE_SYNONYMOUS_VARIANT = 23;
  /*
   * modifier
   */
  // Coding sequence variant.
  CONSEQUENCE_CODING_SEQUENCE_VARIANT = 24;
  // Mature miRNA variant.
  CONSEQUENCE_MATURE_MIRNA_VARIANT = 25;
  // 5' UTR exon variant.
  CONSEQUENCE_FIVE_PRIME_UTR_EXON_VARIANT = 26;
  // 5' UTR intron variant.
  CONSEQUENCE_FIVE_PRIME_UTR_INTRON_VARIANT = 27;
  // 3' UTR exon variant.
  CONSEQUENCE_THREE_PRIME_UTR_EXON_VARIANT = 28;
  // 3' UTR intron variant.
  CONSEQUENCE_THREE_PRIME_UTR_INTRON_VARIANT = 29;
  // Non-coding transcript exon variant.
  CONSEQUENCE_NON_CODING_TRANSCRIPT_EXON_VARIANT = 30;
  // Non-coding transcript intron variant.
  CONSEQUENCE_NON_CODING_TRANSCRIPT_INTRON_VARIANT = 31;
  // Upstream gene variant.
  CONSEQUENCE_UPSTREAM_GENE_VARIANT = 32;
  // Downstream gene variant.
  CONSEQUENCE_DOWNSTREAM_GENE_VARIANT = 33;
  // TFBS ablation.
  CONSEQUENCE_TFBS_ABLATION = 34;
  // TFBS amplification.
  CONSEQUENCE_TFBS_AMPLIFICATION = 35;
  // TFBS binding site variant.
  CONSEQUENCE_TF_BINDING_SITE_VARIANT = 36;
  // Regulatory region ablation.
  CONSEQUENCE_REGULATORY_REGION_ABLATION = 37;
  // Regulatory region amplification.
  CONSEQUENCE_REGULATORY_REGION_AMPLIFICATION = 38;
  // Regulatory region variant.
  CONSEQUENCE_REGULATORY_REGION_VARIANT = 39;
  // Intergenic variant.
  CONSEQUENCE_INTERGENIC_VARIANT = 40;
  // Intron variant.
  CONSEQUENCE_INTRON_VARIANT = 41;
  // Gene variant.
  CONSEQUENCE_GENE_VARIANT = 42;
}

// Consequence-related filter settings.
message QuerySettingsConsequence {
  // The variant types.
  repeated VariantType variant_types = 1;
  // The transcript types.
  repeated TranscriptType transcript_types = 2;
  // List of consequences to consider
  repeated Consequence consequences = 3;
  // Maximal distance to next exon, if any
  optional int32 max_dist_to_exon = 4;
}

// An 1-based integer range.
message Range {
  // 1-based start position.
  int32 start = 1;
  // 1-based end position.
  int32 stop = 2;
}

// Genomic region.
message GenomicRegion {
  // Chromosome
  string chrom = 1;
  // Range of region
  optional Range range = 2;
}

// Locus-related filter settings.
message QuerySettingsLocus {
  // List of HGNC identifiers for filtration to genes.
  //
  // The server will expand gene panels to gene lists here.
  repeated string genes = 1;
  // List of genomic regions to limit restrict the resulting variants to
  repeated GenomicRegion genome_regions = 2;
}

// Enumeration of canonical ClinVar germline aggregte descriptions.
enum ClinvarGermlineAggregateDescription {
  // Unknown description.
  CLINVAR_GERMLINE_AGGREGATE_DESCRIPTION_UNSPECIFIED = 0;
  // Pathogenic.
  CLINVAR_GERMLINE_AGGREGATE_DESCRIPTION_PATHOGENIC = 1;
  // Likely pathogenic.
  CLINVAR_GERMLINE_AGGREGATE_DESCRIPTION_LIKELY_PATHOGENIC = 2;
  // Uncertain significance.
  CLINVAR_GERMLINE_AGGREGATE_DESCRIPTION_UNCERTAIN_SIGNIFICANCE = 3;
  // Likely benign.
  CLINVAR_GERMLINE_AGGREGATE_DESCRIPTION_LIKELY_BENIGN = 4;
  // Benign.
  CLINVAR_GERMLINE_AGGREGATE_DESCRIPTION_BENIGN = 5;
}

// Clinvar-related query settings.
message QuerySettingsClinVar {
  // Wether to require ClinVar membership
  bool presence_required = 1;
  // The ClinVar germline aggregate description to include.
  repeated ClinvarGermlineAggregateDescription germline_descriptions = 2;
  // Whether to include conflicting interpretation ClinVar variants
  bool allow_conflicting_interpretations = 3;
}

// Store query information for one case.
message CaseQuery {
  // Genotype query settings.
  QuerySettingsGenotype genotype = 1;
  // Quality query settings.
  QuerySettingsQuality quality = 2;
  // Frequency query settings.
  QuerySettingsFrequency frequency = 3;
  // Consequence query settings.
  QuerySettingsConsequence consequence = 4;
  // Locus query settings.
  QuerySettingsLocus locus = 5;
  // ClinVar query settings.
  QuerySettingsClinVar clinvar = 6;
}