Pathogenicity scoring system for human clinical genetics

Abstract

Provided are methods and systems for determining the clinical significance of a genetic variant. The methods entail determining, for the variant, (a) a function score based on known impact of the variant on a biological function of a cell or protein, (b) a frequency score based on the frequency of the variant in a population, (c) a co-occurrence score based on how the variant co-occurs with a reference variant having known clinical significance relating to a clinical disease or condition, and (d) a family segregation score based on how the variant segregates with a disease or condition in a family; and aggregating, on a computer, the function score, the frequency score, the co-occurrence score, the family segregation score to generate a clinical significance score indicating the clinical significance of the genetic variant.

1 - 23 . (canceled) 
     
     
         24 . A method, comprising,
 receiving, by a computing device, a plurality of scores associated with a genetic variant;   aggregating, by the computing device, the plurality of scores to generate a clinical significance score indicating a clinical significance of the genetic variant; and   determining that the generated clinical significance score for the variant is above a threshold; and   wherein an individual identified as having the variant or an immediate blood relative of the individual identified as having the variant is tested for a condition associated with the biological function of the cell or protein, responsive to the determination that the generated clinical significance score for the variant is above the threshold.   
     
     
         25 . The method of  claim 24 , wherein aggregating the plurality of scores further comprises summing up, by the computing device, the plurality of scores with pre-determined weights. 
     
     
         26 . The method of  claim 24 , wherein aggregating the plurality of scores further comprises retrieving, by the computing device, a value for the clinical significance score from a leaf node of a decision tree, wherein each score of the plurality of scores is associated with an internal node of the decision tree. 
     
     
         27 . The method of  claim 26 , wherein a first value of a first score of the plurality of scores is associated with a first branch of the internal node of the decision tree corresponding to the first score. 
     
     
         28 . The method of  claim 27 , wherein the internal node of the decision tree corresponding to the first score has at least three branches corresponding to distinct values of the first score. 
     
     
         29 . The method of  claim 26 , wherein the decision tree comprises at least one leaf node at a first layer of the decision tree, and at least one leaf node at a second, higher layer of the decision tree. 
     
     
         30 . The method of  claim 24 , further comprising, responsive to the generated clinical significance score being above a first threshold and below a second threshold, aggregating a second plurality of scores to generate a second clinical significance score;
 wherein at least one of the second plurality of scores is based on new data accumulated after generating the clinical significance score.   
     
     
         31 . The method of  claim 24 , further comprising excluding a second variant from an output report, responsive to a generated clinical significance score of the second variant being below the threshold. 
     
     
         32 . The method of  claim 24 , wherein the plurality of scores comprise at least two of a function score based on known or projected impact of the variant on a biological function of a cell or protein; a frequency score based on the frequency of the variant in a population; a co-occurrence score based on how the variant co-occurs with a reference variant having known clinical significance relating to a clinical disease or condition; a family segregation score based on how the variant segregates with a disease or condition in a family; and a minor evidence score based on information from at least one functional impact prediction algorithm, whether the variant occurs within a critical protein domain, whether the variant would alter a post-translational modification, whether other known pathogenic variants occur within the same codon, and whether the variant is known to occur in at least one patient of a disease or condition. 
     
     
         33 . The method of  claim 32 , further comprising retrieving, by the computing device from a database comprising a plurality of variants and associated patients, co-occurrence or family segregation data for the variant. 
     
     
         34 . A system, comprising:
 a computing device comprising a processor configured to:
 receive a plurality of scores associated with a genetic variant, 
 aggregate the plurality of scores to generate a clinical significance score indicating a clinical significance of the genetic variant, and 
 determine that the generated clinical significance score for the variant is above a threshold; and 
   wherein an individual identified as having the variant or an immediate blood relative of the individual identified as having the variant is tested for a condition associated with the biological function of the cell or protein, responsive to the determination that the generated clinical significance score for the variant is above the threshold.   
     
     
         35 . The system of  claim 34 , wherein the computing device is further configured to sum up the plurality of scores with pre-determined weights. 
     
     
         36 . The system of  claim 34 , wherein the computing device is further configured to retrieve a value for the clinical significance score from a leaf node of a decision tree, wherein each score of the plurality of scores is associated with an internal node of the decision tree. 
     
     
         37 . The system of  claim 36 , wherein a first value of a first score of the plurality of scores is associated with a first branch of the internal node of the decision tree corresponding to the first score. 
     
     
         38 . The system of  claim 37 , wherein the internal node of the decision tree corresponding to the first score has at least three branches corresponding to distinct values of the first score. 
     
     
         39 . The system of  claim 36 , wherein the decision tree comprises at least one leaf node at a first layer of the decision tree, and at least one leaf node at a second, higher layer of the decision tree. 
     
     
         40 . The system of  claim 34 , wherein the computing device is further configured to, responsive to the generated clinical significance score being above a first threshold and below a second threshold, aggregate a second plurality of scores to generate a second clinical significance score;
 wherein at least one of the second plurality of scores is based on new data accumulated after generating the clinical significance score.   
     
     
         41 . The system of  claim 34 , wherein the computing device is further configured to exclude a second variant from an output report, responsive to a generated clinical significance score of the second variant being below the threshold. 
     
     
         42 . The system of  claim 34 , wherein the plurality of scores comprise at least two of a function score based on known or projected impact of the variant on a biological function of a cell or protein; a frequency score based on the frequency of the variant in a population; a co-occurrence score based on how the variant co-occurs with a reference variant having known clinical significance relating to a clinical disease or condition; a family segregation score based on how the variant segregates with a disease or condition in a family; and a minor evidence score based on information from at least one functional impact prediction algorithm, whether the variant occurs within a critical protein domain, whether the variant would alter a post-translational modification, whether other known pathogenic variants occur within the same codon, and whether the variant is known to occur in at least one patient of a disease or condition. 
     
     
         43 . The system of  claim 42 , wherein the computing device is further configured to retrieve, from a database comprising a plurality of variants and associated patients, co-occurrence or family segregation data for the variant.