rank_modelv1.18

Genmod score uses the weighted sum model (WSM) approach to rank the most likely pathogenic variant.

Generally, the higher value the more likely pathogenic variant.

Genmod_score uses config files to define the rank model, which enables customized set-up and versioning of rank models.

The WSM uses the following alternatives and weights in the rank model:

Rank score range: -33 <= rs <= 44

Consequence

Each alleles variant effect on individual transcripts are evaluated using a rule-based approach defined by SO-terms. The SO-terms themselves are ranked in order of severity and this ranking is used to defined the weight of the consequence alternative. The performance score is based on the most severe consequence within each gene.

Performance value for the SO-terms:

• transcript_ablation = 10
• initiator_codon_variant = 9
• frameshift_variant = 8
• stop_gained = 8
• start_lost = 8
• stop_lost = 8
• splice_acceptor_variant = 8
• splice_donor_variant = 8
• inframe_deletion = 5
• transcript_amplification = 5
• splice_region_variant = 5
• missense_variant = 5
• protein_altering_variant = 5
• inframe_insertion = 5
• incomplete_terminal_codon_variant = 5
• non_coding_transcript_exon_variant = 3
• synonymous_variant = 2
• mature_miRNA_variant = 1
• non_coding_transcript_variant = 1
• regulatory_region_variant = 1
• upstream_gene_variant = 1
• regulatory_region_amplification = 1
• TFBS_amplification = 1
• 5_prime_UTR_variant = 1
• intron_variant = 1
• 3_prime_UTR_variant = 1
• feature_truncation = 1
• TF_binding_site_variant = 1
• stop_retained_variant = 1
• feature_elongation = 1
• regulatory_region_ablation = 1
• TFBS_ablation = 1
• coding_sequence_variant = 1
• downstream_gene_variant = 1
• NMD_transcript_variant = 1
• intergenic_variant = 0
• not_reported = 0

Frequency

The alternative allele frequency (AF) in public databases (1000G, ExAC, MTAF, SWEREF). The highest reported alternative frequency and observation count (locusDB) reported from the databases is used to calculate the performance value.

Definitions:

• Not reported: AF Na
• Very Rare: AF < 0.0005
• Rare: 0.0005 <= AF < 0.005
• Intermediate: 0.005 <= AF < 0.02
• Common: AF >= 0.02

Performance value for maximum AF:

• Not reported = 4
• Very rare = 3
• Rare = 2
• Intermediate = 1
• Common = -12

Observation Count

The observation count (Obs) from the local variant database locusDB.

Definitions:

• Not reported: Obs Na
• Very Rare: Obs < 5
• Rare: 5 <= Obs < 10
• Intermediate: 10 <= Obs < 20
• Common: Obs >= 20

Performance value for maximum Obs:

• Not reported = 4
• Very Rare = 3
• Rare = 2
• Intermediate = 1
• Common = -12

Inheritance Model(s)

The segregation pattern for the variant within the family. These models are currently annotated using genmod models. A variant that is annotated as autosomal compound with no compound partner with a rank score greater than 10 will receive a penalty of -6 to the variants rank score. For single samples this rule will be enforced for variants with inheritance model autosomal dominant, autosomal dominant denovo in addition to the autosomal compound annotation.

Definitions:

• Autosomal Recessive, denoted ‘AR_hom’
• Autosomal Recessive denovo, denoted ‘AR_hom_dn’
• Autosomal Dominant, ‘AD’
• Autosomal Dominant denovo, ‘AD_dn’
• Autosomal Compound Heterozygote, ‘AR_comp’
• X-linked dominant, ‘XD’
• X-linked dominant de novo, ‘XD_dn’
• X-linked Recessive, ‘XR’
• X-linked Recessive de novo, ‘XR_dn’

Performance value for inheritance models:

• Valid model = 1
• No model = -12
• AR_comp penalty = -6

Protein Functional Prediction

The predicted functional effect on the protein. Currently 2 protein effect predictors are used (Sift, PolyPhen2). Each predictors can contribute 1 point each to the overall protein predictor performance score.

SIFT predicts whether an amino acid substitution is likely to affect protein function based on sequence homology and the physico-chemical similarity between the alternate amino acids [1].

PolyPhen-2 predicts the effect of an amino acid substitution on the structure and function of a protein using sequence homology, Pfam annotations, 3D structures from PDB where available, and a number of other databases and tools (including DSSP, ncoils etc [2].

Definitions:

• Sift Terms:
  • “D” Deleterious (score<=0.05)
  • “T” Tolerated (score>0.05)
• PolyPhen2HumVar Terms:
  • “D”: Probably damaging (>=0.909)
  • “P”: Possibly damaging (0.447<=pp2_hvar<=0.909)
  • “B”: Benign (pp2_hvar<=0.446)

Performance value for protein predictors:

• Sift:
  • D = 1
• PolyPhen2HumVar:
  • D or P = 1

Gene Intolerance Score

EXAC gene intolerance score - calculated by VEP’s LoFtool plugin.

Definitions:

• Not reported: LoFtool Na
• Low: LoFtool < 0.0001
• Medium: 0.0001 <= LoFtool < 0.01
• High LoFtool < 0.01

Performance value for gene intolerance score:

• Not reported = 0
• Low = 2
• Medium = 1
• High = 0

Variant Quality Filter

Each variant call has a filter tranche attached to it indicating the quality of the actual variant call.

Definitions:

• PASS
• Other (Tranches e.g. For GATK [3]: “VQSRTrancheBOTH99.90to100.00”

We also evaluate the combined GQ score called a Model score for reducing the impact of poor quality genotypes across a case.

Definitions:

• Low quality (GQ => 20)
• High quality (GQ > 20)

Performance value for variant quality filter:

• Filter tranche:

  • PASS = 3
  • Other = 0

• Model score:

  • Low quality = -5
  • High quality = 0

Conservation

The level of conservation for a sequence element (PhastCons [4]), nucleotides or classes of nucleotides PhyloP [5] both from the Phast [6] package as well as genomic constraint score GERP [7] is used. The Phast datasets used in the conservation calculation were generated by the UCSC/Penn State Bioinformatics comparative genomics alignment pipeline. A description of this analysis can be found at UCSC. Each type of conservation can contribute 1 point each to the overall conservation performance score.

Definitions:

• Conserved
  • PhastCons: 0.8 >= Score <= 1
  • GERPRS: Score >= 2
  • PhyloP: Score > 2,5

Performance value for conservation:

• Conserved:
  • PhastCons100way_vertebrate = 1
  • PhyloP100way_vertebrate = 1
  • GERP++RS = 1

Combined Annotation Dependent Depletion (CADD)

CADD is a tool for scoring the deleteriousness of single nucleotide variants as well as insertion/deletions variants in the human genome. C-scores strongly correlate with allelic diversity, pathogenicity of both coding and non-coding variants, and experimentally measured regulatory effects, and also highly rank causal variants within individual genome sequences. The CADD-score is a pre-calculated for all SNVs and for indel from 1000G-project [8].

Definitions:

• Strongly deleterious (CADD > 40)
• deleterious (40 >= CADD > 30)
• Mildly deleterious (30 >= CADD > 20)
• Probably deleterious (20 >= CADD > 10)
• Benign (10 >= CADD >= 0)

Performance value for CADD:

• Strongly deleterious = 5
• Deleterious = 4
• Mildly deleterious = 3
• Probably deleterious = 2
• Benign = 0

ClinVar

ClinVar [9] is a freely accessible, public archive of reports of the relationships among human variations and phenotypes, with supporting evidence. Each variant in clinvar has a record of clinical significance (CLNSIG):

Definitions:

• Uncertain significance = 0
• Not provided = 1
• Benign = 2
• Likely benign = 3
• Likely pathogenic = 4
• Pathogenic = 5
• Drug response = 6
• Histocompatibility = 7
• Other = 255

Performance value for ClinVar:

• Uncertain significance = 0
• Not provided = 0
• Benign = -1
• Likely benign = 0
• Likely pathogenic = 2
• Pathogenic = 5
• Drug response = 0
• Histocompatibility = 0
• Other = 0

Clinical review status

Clinical review status (CLNREVSTAT) is a measure on the certainty of the supporting evidence for the variant’s clinical significance.

Definitions:

• not_reported
• no_assertion
• no_criteria
• single
• mult
• conf
• exp
• guideline

Performance value for CLNREVSTAT:

• not_reported = 0
• no_assertion = 0
• no_criteria = 0
• single = 1
• conf = 1
• mult = 2
• exp = 3
• guideline = 4

Spidex

Spidex is a database for snvs that have been predicted to affect splicing.

Definitions:

• Not reported = 0
• Low (-1 < dpsi < 1)
• Medium (-1 <= dpsi > 1 & -2 > dpsi < 2)
• High (-2 <= dpsi >= 2)

Performance value for Spidex:

• Low = 0
• Medium = 3
• High = 5