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Clinical trials are listed in this when one of the knowledge bases determines the trial to be a match for the variant. The information in this table is from the clinical trial database.
By default, the assertions are filtered by the case and ancestor diseases. Ancestor diseases are determined using SNOMEDCT. These diseases can be viewed at the SNOMED CT Browser website, with the following exceptions:
Descendents of neoplastic disease do not include ancestors beyond neoplastic disease.
Non-small cell lung cancer has been added as an ancestor of adenocarcinoma of lung.
You can also filter by other diseases, title, city, state, and country.
Filter changes are saved and applied across variants within a case and can be reset if needed.
Connected Insights provides access to the National Library of Medicine Clinical Trials website, which provides information on publicly and privately supported clinical studies on a wide range of diseases and conditions.
The following from JAX-CKB are not currently supported:
Clinical trials with a recruitment status of completed, withdrawn, or active, not recruiting.
Variants that have the excluded requirement type.
The software does not yet determine if a case has all the requirements for a clinical trial (for example, a clinical trial requires two variants).
The Biomarker Details page brings together key information and actions related to variants. The page exists for individual variants and genome-wide biomarkers like TMB and MSI. You can use the Biomarker Details page to do the following:
Interpret the variant and include it in the report.
Review assertions already created for the variant. For more information, refer to .
Review sign-off reports that included the variant. For more information, refer to .
Review variant information related to oncology: – Knowledge bases. For more information, refer to . – Clinical trials. For more information, refer to .
Review variant information. For more information, refer to Variant Overview. – Annotation details – Gene information – Records in external sources – Functional impact predictions – Population frequency
Set gene transcripts. For more information, refer to .
To open the Biomarker Details page, select Interpret for a specific variant in the Overview or Variants tab.
This section provides details on the variant’s presence in different datasets.
Displays the number of samples with the variant in the given workgroup presented per disease. To be accounted for, the variant:
Need to be present in any uploaded VCF or variant file
Need to have a flag PASS in the VCF variant filters
Doesn’t need to be interpreted or included in the report
Can have any variant origin (predicted germline or suspected somatic)
❗ Cases processed prior to version 4.0 of Connected Insights will not appear in the lab frequency.
The section displays:
Number of samples in the with the variant for the selected transcript
Highest number of samples in the for the variant across transcripts
The section displays:
Genomic Mutation ID in the COSMIC database
Number of samples with the variant in the COSMIC database displayed per cancer site, for example, breast
Number of samples with the variant in the COSMIC database displayed per histology, for example, carcinoma
Field Name
Description
Column
Description
Update Date
The last date that the assertion was updated.
Source
Knowledge base origin of the clinical trial.
Status
Indicates the TMB, MSI, or GIS status for the clinical trial. This column is available for TMB, MSI,and GIS.
HRD
Indicates whether a clinical trial is associated with HRD positive or negative. This column is available for GIS and variants, when the selected transcript is for BRCA1/2.
Biomarker
Indicates how the assertion is related to the variant (for example, specific amino acid change or specific exon change).
Title
Title of the clinical trial.
Phase
Phase of the clinical trial.
Location
Location of the clinical trial.
Disease
Disease for the clinical trial.
Actions
This column contains the following available actions: • Select the hyperlink to display the full listing about the trial in a new browser tab. • Add to report • Archive, if the assertion is in My Knowledge Base • Copy to New Assertion, if the assertion is not in My Knowledge Base • View past cases To edit an assertion, add it to the report before editing. For more information, refer to Manage Assertions.
Lists the allele count, allele number, number of homozygotes, and allele frequency for each population from gnomAD for small variants and 1000 Genomes for copy number variants and structural variants. This section is only available for variants.
The Oncogenicity Prediction feature estimates oncogenic potential of variants based on Standards for the classification of somatic variants in cancer (Horak et al., Genet Med. 2022). The standards include 17 criteria and allow to classify variants into 5 categories: Oncogenic, Likely Oncogenic, Variant of Unknown Significance (VUS), Likely Benign, and Benign. Connected Insights scores variants (only PASS small variants are currently supported) for 16 criteria (with exception of OP2) based on the implementation details provided below.
❗ Use predictions as a starting point for interpretation. Exercise judgement to determine if a greater or fewer number of criteria apply.
Estimated variant oncogenicity can be found:
In the column “Oncogenicity Prediction” in the Variants tab available for sorting
In the section “Oncogenicity Prediction” in the Biomarker page available for manual review and further interpretation
To view the evidence behind the estimated oncogenicity category and complete variant classification, follow the steps below:
Navigate to the "Oncogenicity Prediction" section in the Biomarker page
Review estimated oncogenicity category, score, and met criteria (displayed with filled checkboxes, see OS2, OM1, OM2, OP3, and OP4 on the figure below)
Review evidence for each criterion by clicking on it and displaying an evidence map. You can move objects on the map to facilitate review.
Select Report to edit and complete variant classification following Interpret a Variant. Information about met oncogenicity criteria is used to pre-populate variant summary.
OVS1: “Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a bona fide tumor suppressor gene.”
For this criterion, we are checking the fulfillment of the following conditions:
Variant is a “null variant”. We assess null variants as variants with consequences stop_gained, start_lost, frameshift_variant, splice_acceptor_variant, or splice_donor_variant as well as variants with a high splicing prediction (SpliceAI score > 0.8) regardless of their consequences
Variant is not in the last intron or exon
Variant is in a tumor suppressor gene, according to Cancer Genome Census, JAX-CKB, OncoKB or MyKB
OS1: “Same amino acid change as a previously established oncogenic variant regardless of nucleotide change. Example: Val→Leu caused by either G>C or G>T in the same codon.”
For this criterion, we are checking the fulfillment of the following conditions:
Variant's consequences are not splice_donor_variant or splice_acceptor_variant
Variant’s splicing prediction is not high (SpliceAI score <= 0.8)
There is a previously established pathogenic / oncogenic or likely pathogenic / oncogenic variant with the same amino acid change but different nucleotide change in ClinVar (2-4 stars) or MyKB
OS2: “Well-established in vitro or in vivo functional studies supportive of an oncogenic effect of the variant.”
For this criterion, we are checking the fulfillment of the following conditions:
A variant with the same amino acid change is a gain-, loss-, or switch-of-function variant in MyKB, OncoKB, or JAX-CKB, is interpreted as pathogenic / oncogenic or likely pathogenic / oncogenic in MyKB, OncoKB, JAX-CKB, or ClinVar (2-4 stars), and OS1 is not applicable OR
A variant with the same nucleotide change is a gain-, loss-, or switch-of-function variant in MyKB, OncoKB, or JAX-CKB, is interpreted as pathogenic / oncogenic or likely pathogenic / oncogenic in ClinVar (2-4 stars), and OS1 is applicable
In this implementation, “Well-established in vitro or in vivo functional studies” is inferred based on knowledge bases having records of gain-, loss-, or switch-of-function, usually established based on functional studies. “... supportive of an oncogenic effect of the variant” is established based on the evidence of oncogenicity in knowledge sources.
OS3: “Located in one of the hotspots in cancerhotspots.org with at least 50 samples with a somatic variant at the same amino acid position, and the same amino acid change count in cancerhotspots.org in at least 10 samples.”
For this criterion, we are checking the fulfillment of the following conditions:
There are at least 50 samples with somatic variants at the same amino acid position in cancerhotspots.org, there are at least 10 samples with variants with the same amino acid change in cancerhotspots.org and OS1 is not applicable OR
There are at least 50 samples with somatic variants at the same amino acid position in COSMIC, there are less than 10 samples with variants with the same amino acid change in cancerhotspots.org and OS1 is not applicable OR
There are at least 50 samples with somatic variants at the same nucleotide position in cancerhotspots.org, there are at least 10 samples with a variant with the same nucleotide change in cancerhotspots.org and OS1 is applicable OR
There are at least 50 samples with somatic variants at the same nucleotide position in COSMIC, there are less than 10 samples with a variant with the same nucleotide change in cancerhotspots.org and OS1 is applicable
OM1: “Located in a critical and well-established part of a functional domain (e.g., active site of an enzyme).”
For this criterion, we are checking the fulfillment of the following conditions:
The variant is located in a region of a protein domain where pathogenic variants occur. The regions in each gene are defined by taking all protein domains from UniProt, mapping all pathogenic and likely pathogenic variants in ClinVar to each domain and defining the regions by using the positions of the first and last pathogenic and likely pathogenic variants from ClinVar and adding 2 bp padding on each side.
OS1 and OS3 are not applicable
OM2: “Protein length changes as a result of in-frame deletions / insertions in a known oncogene, or tumor suppressor gene or stop-loss variants in a known tumor suppressor gene.”
For this criterion, we are checking the fulfillment of the following conditions:
Variant’s consequence is inframe_deletion or inframe_insertion and it is located in an oncogene or a tumor suppressor gene (based on Cancer Genome Census, JAX-CKB, OncoKB or MyKB) or variant’s consequence is stop-lost and it is located in a tumor suppressor gene per the same sources
OVS1 is not applicable
OM3: “Located in one of the hotspots in cancerhotspots.org with less than 50 samples with a somatic variant at the same amino acid position, and the same amino acid change count in cancerhotspots.org is at least 10.”
For this criterion, we are checking the fulfillment of the following conditions:
There are less than 50 samples with somatic variants at the same amino acid position in cancerhotspots.org, there are at least 10 samples with variants with the same amino acid change in cancerhotspots.org , and OM1 and OM4 are not applicable OR
There are 10 - 49 samples with somatic variants at the same amino acid position and change in COSMIC, there are less than 10 samples with variants with the same amino acid change in cancerhotspots.org , and OM1 and OM4 are not applicable
OM4: “Missense variant at an amino acid residue where a different missense variant determined to be oncogenic (using this standard) has been documented. Amino acid difference from reference amino acid should be greater or at least approximately the same as for missense change determined to be oncogenic.”
For this criterion, we are checking the fulfillment of the following conditions:
There is a missense variant at the same amino acid position with a different amino acid change interpreted as pathogenic / oncogenic or likely pathogenic / oncogenic in ClinVar (2-4 stars), OncoKB or MyKB
OS1, OS3 and OM1 are not applicable
OP1: “All utilized lines of computational evidence support an oncogenic effect of a variant (conservation / evolutionary, splicing impact, etc.).”
For this criterion, we are checking the fulfillment of the following conditions:
Variant’s effect predicted to be damaging (REVEL > 0.75 and PrimateAI-3D score percentile > 0.8) or variant’s splicing prediction is high (SpliceAI score > 0.8)
OP2: “Somatic variant in a gene in a malignancy with a single genetic etiology.”
This criterion is not yet implemented.
OP3: “Located in one of the hotspots in cancerhotspots.org and the particular amino acid change count in cancerhotspots.org is below 10.”
For this criterion, we are checking the fulfillment of the following conditions:
There is at least 1 sample with a somatic variant at the same amino acid position in cancerhotspots.org or COSMIC
There are less than 10 samples with variants with the same amino acid change in both, cancerhotspots.org and COSMIC
OP4: “Absent from controls (or at an extremely low frequency) in Genome Aggregation Database (gnomAD).”
For this criterion, we are checking the fulfillment of the following conditions:
Variant’s allele count in the global population (gnomAD) is less than 10 if the variant is not in TP53, KRAS, or PTEN
Variant is absent in the global population (gnomAD) if the variant is in TP53 or KRAS
Variant’s frequency in the global population is less than 0.001% (gnomAD) if the variant is in PTEN
SBVS1: “Minor allele frequency is >5% in Genome Aggregation Database (gnomAD) in any of 5 general continental populations: African, East Asian, European (Non-Finnish), Latino, and South Asian.”
For this criterion, we are checking the fulfillment of the following conditions:
Variant’s frequency in any one population is over 5% (gnomAD) if the variant is not in TP53, KRAS or PTEN
Variant’s frequency in the global population is equal or over 0.1% (gnomAD) and allele count in the global population is equal or over 5 (gnomAD) if the variant is in TP53
Variant’s frequency in the global population is equal or over 0.05% (gnomAD) if the variant is in KRAS
Variant’s frequency in the global population is equal or over 1% (gnomAD) and allele count in the global population is equal or over 5 (gnomAD) if the variant is in PTEN
SBS1: “Minor allele frequency is >1% in Genome Aggregation Database (gnomAD) in any of 5 general continental populations: African, East Asian, European (Non-Finnish), Latino, and South Asian.”
For this criterion, we are checking the fulfillment of the following conditions:
Variant’s frequency in any one population is over 1% (gnomAD) if the variant is not in TP53, KRAS or PTEN
Variant’s frequency in the global population is over 0.03% (gnomAD) and allele count in the global population is equal or over 5 (gnomAD) if the variant is in TP53
Variant’s frequency in the global population is equal or over 0.025% (gnomAD) if the variant is in KRAS
Variant’s frequency in the global population is equal or over 0.1% (gnomAD) and allele count in the global population is equal or over 5 (gnomAD) if the variant is in PTEN
SBS2: “Well-established in vitro or in vivo functional studies show no oncogenic effects.”
For this criterion, we are checking the fulfillment of the following conditions:
Variant is interpreted as benign or likely benign in ClinVar (2-4 stars), OncoKB or MyKB
SBP1: “All used lines of computational evidence suggest no effect of a variant (conservation / evolutionary, splicing effect, etc.).”
For this criterion, we are checking the fulfillment of the following conditions:
Variant’s effect predicted to be neutral (REVEL is equal or less than 0.75 and PrimateAI-3D score percentile is equal or less than 0.8)
Variant’s splicing prediction is low or unknown (SpliceAI score is equal or less than 0.2 or unknown)
SBP2: “A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.”
For this criterion, we are checking the fulfillment of the following conditions:
Variant has a consequence synonymous_variant
Variant’s conservation prediction score is not high (PhyloP < 0.1)
Variant’s splicing prediction is low or unknown (SpliceAI score <= 0.2)
A single table in the biomarker details provides a list of all the diagnostic assertions from all included sources that have content about the biomarker (e.g., My Knowledge Base).
You can filter by other diseases or by summary. When filtering by summary for guideline evidence, specify the website (for example, ESMO.org or NCCN.org).
Filter changes are saved and applied across variants within a case and can be reset if needed.
A single table in the biomarker details provides a list of all the therapeutic and prognostic assertions from all included sources that have content about the biomarker (e.g., My Knowledge Base).
By default, the assertions are filtered by the case and ancestor diseases. Ancestor diseases are determined using SNOMEDCT. These diseases can be viewed at the , with the following exceptions:
Descendents of neoplastic disease do not include ancestors beyond neoplastic disease.
Non-small cell lung cancer has been added as an ancestor of adenocarcinoma of lung.
You can filter by other diseases, by summary, or by approval. When filtering by summary for guideline evidence, specify the website (for example, ESMO.org or NCCN.org).
Filter changes are saved and applied across variants within a case and can be reset if needed.
Connected Insights provides the Memorial Sloan Kettering OncoKB. For more information, refer to the OncoKB website.
The following from OncoKB are not supported:
Non-compliant HGVS
Unspecified positions: Epigenetic Silencing, ARv567es, AR-V7, DNMT3B7, vIII, vII, vV, TGFBR1*6A, Overexpression, Wildtype, Promoter Hypermethylation, Hypermethylation, Kinase Domain Duplication, Internal Tandem Duplication, Partial Tandem Duplication
Connected Insights provides the Jackson Clinical Knowledge Base (JAX-CKB). For more information, refer to the Jackson CKB website.
The following from JAX-CKB are not supported:
Complex molecular profiles (for example, co-occuring biomarker assertions)
Emerging and risk factor evidence types
Class #, over exp, dec exp, hypermethylation, hypomethylation, dup exonX, dup exonX-X, LOH, loss, negative (except for HRD andMSI), positive (except for HRD), and wild type variants.
Connected Insights also provides the Clinical Interpretation of Variants in Cancer (CIViC) knowledge base. For more information, refer to the CIViC website.
The following from CIViC are not supported:
Assertions
Functional and oncogenic evidence types
Splice Site (c.3028G>A), Boolean-like evidence (for example, (V600E or V600K) and Amplification), Underexpression, Overexpression, Expression, Decreased Peri-therapeutic Expression, Cytoplasmic Expression, Loss, Biallelic Inactivation, Alu Insertion, Alternative Transcript, RSID, Homozygosity, Copy-neutral Loss of Heterozygosity, Cytoplasmic Mislocation, Deleterious Mutation, Double Ph, Wildtype, Domain, Exon-specific fusions
The Biological Classification section of the Biomarker Details page summarizes all biological assertions previously created for the variant across all sources (e.g., My Knowledge Base or JAX-CKB). If you have existing knowledge to upload to the system, refer to .
You can also filter by other diseases and by summary.
Filter changes are saved and applied across variants within a case and can be reset if needed.
Connected Insights provides the Memorial Sloan Kettering OncoKB. For more information, refer to the OncoKB website.
The following from OncoKB are not supported:
Non-compliant HGVS
Unspecified positions: Epigenetic Silencing, ARv567es, AR-V7, DNMT3B7, vIII, vII, vV, TGFBR1*6A, Overexpression, Wildtype, Promoter Hypermethylation, Hypermethylation, Kinase Domain Duplication, Internal Tandem Duplication, Partial Tandem Duplication
Connected Insights provides the Jackson Clinical Knowledge Base (JAX-CKB). For more information, refer to the Jackson CKB website.
The following from JAX-CKB are not supported:
Complex molecular profiles (for example, co-occuring biomarker assertions)
Emerging and risk factor evidence types
Class #, over exp, dec exp, hypermethylation, hypomethylation, dup exonX, dup exonX-X, LOH, loss, negative (except for HRD andMSI), positive (except for HRD), and wild type variants.
Field Name
Description
VCF Column
Required Value
Variant Type
Type of the variant: SNV, insertion, deletion, MNV
Chromosome
The reference sequence name. Values are #, or chr#, where # is 1 of the following: •The chromosome number, as in 1–22. •The name, as in X or Y; M or MT for mitochondrial.
Start
Start position.
Stop
Stop position.
Variant ID
Variant ID from Nirvana, based on the Broad variant ID scheme.
Ref Allele
The reference allele.
Alt Allele
The alternate allele.
Genes
Name of the gene if applicable. A comma-delimited list is used for multiple genes.
Exons
Exon number(s) and the total exons for the active transcript, as applicable. A comma-delimited list is used for multiple exons.
Cytogenetic Band
Cytoband of variant.
All Consequences
Sequence Ontology consequences to describe how each variant impacts a given transcript.
Field Name
Description
Database
Database Description
IGV
Integrative Genomics Viewer (IGV) is an open-source genome browser and visualization tool used to observe biologically interesting patterns in genomic data sets, including sequence data, gene models, alignments, and data from DNA microarrays.
LOVD
The Leiden Open Variation Database (LOVD) is an open-source database focused on the combination between a gene and a genetic (heritable) disease.
UCSC Browser
An interactive database offering access to genome sequence data from various vertebrate and invertebrate species and major model organisms, integrated with a large collection of aligned annotations.
Ensembl
A bioinformatics project organizing biological information around the sequences of large genomes. It is a comprehensive source of stable automatic annotation of individual genomes, and of the synteny and orthology relationships between them..
gnomAD
A database that aggregates and harmonizes both exome and genome sequencing data from a wide variety of large-scale sequencing projects.
COSMIC
An online database of somatically acquired mutations found in human cancer. This link opens COSMIC in a new browser tab.
Google Scholar
Google Scholar provides a way to broadly search for scholarly literature. Search across many disciplines and sources, including: • Articles • Theses • Books • Abstracts This information comes from academic publishers, professional societies, online repositories, universities, and other web sites.
PubMed
PubMed allows you to search for literature for the variant.
LitVar
LitVar allows you to search for literature for the variant. This is available for any variant with an RSID.
Mastermind
Mastermind allows you to search for literature for the variant. This is available for any variant with an hgvsg annotation.
This section presents a visualization of the variant in the genome with supporting annotations and surrounding variants.
Reference — Reference genome base pair proportions when zoomed out. Base pair letters and amino acids for a given reading frame when zoomed in.
Genes — RefSeq gene track. Blue indicates the - strand and red indicates the + strand. Click a gene to show the reading frame of the selected transcript for the variant (amino acid and position).
Protein Domains — Displays protein domains from UniProt. Blue indicates the - strand and red indicates the + strand.
Small variants — Small variants shown with the reference allele on top and the two alt alleles below.
Structural variants — Structural variants with VCF filter PASS by chromosomal position. The legend to the right of the genome view identifies the events (translocation, inversion, deletion, insertion, and tandem duplication). Translocations begin at the karyogram at the top of the track and connect to chromosomes identified at the bottom of the track.
Coverage and copy number variants — The depth of coverage by chromosomal position. Data points are color-coded by presence of copy number variant calls. The legend identifies the events (gain, gain LOH, neutral LOH, loss, and no call). Hovering over a region will highlight the copy number variant call and clicking provides variant details.
B-allele ratio — The minor allele frequency by chromosomal position.
Track availability depends on the VCFs provided by the secondary analysis pipeline.
For example,
If there's no structural variant VCF provided, then the structural variant track will not be available.
If there's no absolute copy number provided in the VCF, then the copy number variant track will not be available.
To pan, use the pan controls at the top of the section, or click and drag one of the tracks left or right.
To zoom, use the zoom controls at the top of the section, or hold ctrl and scroll with your mouse or trackpad.
Field Name | Description |
Column | Description |
Published Date | The date that the assertion was updated. |
Source | Knowledge base origin of the assertion. |
Biomarker | Indicates whether an assertion is the nucleotide, annotation overlap, partial fusion, amino acid,codon, exon, or gene level. This column is only available for variants. |
Status | Indicates the TMB, MSI, or GIS status for the assertion. This column is available for TMB, MSI, and GIS. |
HRD | Indicates whether an assertion is associated with HRD positive or negative. This column is available for GIS and variants when the selected transcript is for BRCA1/2. |
Classification | This column displays the classification (for example, Tier 1A), as indicated by the knowledge base. |
Type | Therapeutic, Diagnostic, or Prognostic as indicated by the knowledge base. |
Direction | • For therapeutic; responsive, nonresponsive, etc., as indicated by the knowledge base. • For prognostic; favorable, unfavorable, etc., as indicated by the knowledge base. |
Therapy | Therapy for the assertion. |
Disease | Disease for the assertion. |
Approval | Authorities that have approved the therapy for the biomarker and disease. • CKB provides FDA, EMA, ANVISA, PDMA, and TGA approvals. • OncoKB level 1 assertions are annotated with FDA. |
Actions |
Field Name | Description |
Column | Description |
Directional Arrows | Opens to view the assertion summary. |
Update Date | The last date that the assertion was updated. |
Biomarker | Indicates how the assertion is related to the variant (for example, specific amino acid change or specific exon change). |
HRD | Indicates whether an assertion is associated with HRD positive or negative. This column is available for GIS and variants when the selected transcript is for BRCA1/2. |
Classification | This column displays the classification as indicated by the knowledge base. |
Type | The assertion type (for example, biological). For more information, refer to Interpret a Variant. |
Disease | The disease associated with the classification. |
Actions |
This section is only available for variants that overlap a transcript.
A list of all genes overlapping the variant are provided. Select one to view the details below.
Column | Description |
---|---|
Memorial Sloan Kettering OncoKB
Connected Insights provides the Memorial Sloan Kettering OncoKB. For more information, refer to the OncoKB website.
Jackson Clinical Knowledge Base (JAX-CKB)
Connected Insights provides the Jackson Clinical Knowledge Base (JAX-CKB). For more information, refer to the Jackson CKB website.
Clinical Interpretation of Variants in Cancer (CIViC)
Connected Insights also provides the Clinical Interpretation of Variants in Cancer (CIViC) knowledge base. For more information, refer to the CIViC website.
The associated phenotypes in ClinGen and OMIM databases and links to open the entries in the databases in a new browser tab.
The following external links are included in this section:
PubMed
MGI
DECIPHER
GeneReviews
Monarch
ZFIN
STRING
This column contains the following available actions: • Add to report • Archive, if the assertion is in My Knowledge Base • Copy to New Assertion, if the assertion is not in My Knowledge Base • View past cases To edit an assertion, add it to the report before editing. For more information, refer to .
This column contains the following available actions: • Add to report • Archive, if the assertion is in My Knowledge Base • Copy to New Assertion, if the assertion is not in My Knowledge Base • View past cases To edit an assertion, add it to the report before editing. For more information, refer to .
Update Date
The last date that the assertion was updated.
Source
Knowledge base origin of the gene description.
Role
The specified gene role.
Summary
Gene description.
Actions
This column contains the following available actions: • Add to report • Archive, if the assertion is in My Knowledge Base • Copy to New Assertion, if the assertion is not in My Knowledge Base • View past cases To edit an assertion, add it to the report before editing. For more information, refer to Manage Assertions.
Field Name | Description |
Tool | Description |
REVEL | The Rare Exome Variant Ensemble Learner (REVEL) is an ensemble method for predicting the pathogenicity of rare missense variants. Scores range from 0 to 1 and variants with highers cores are predicted to be more likely to be pathogenic. |
SIFT | The Sort Intolerant From Tolerant (SIFT) score predicts whether an amino acid substitution is likely to affect protein function based on sequence homology and the physicochemical similarity between the alternate amino acids. The qualitative prediction for substitutions with a score less than 0.05 are predicted to be deleterious. All other variants are considered tolerated. |
PolyPhen-2 | Polymorphism Phenotyping-2, or PolyPhen-2, predicts the effect of an amino acid substitution on the structure and function of a protein using the following components: • Sequence homology • Pfam annotations • 3D structures from PDB (where available) • Other databases and tools (for example, DSSP and ncoils) The PolyPhen-2 score represents the probability that a substitution is damaging, so values near1 are predicted to be deleterious, which is the opposite of the SIFT score. |
PrimateAI | PrimateAI is a deep residual neural network for classifying the pathogenicity of missense mutations. For more information, refer to . |
PrimateAI-3D | PrimateAI-3D is a three-dimensional (3D) convolutional neural network for classifying the pathogenicity of missense mutations. For more information, refer to . |
Nirvana Cross-SpeciesAA Conservation | Nirvana Cross-Species AA Conservation uses amino acid conservation scores that are obtained from multiple alignments of vertebrate exomes to the human ones. The score indicates the frequency with which a particular AA is observed in humans. |
PhyloP | PhyloP scores measure evolutionary conservation at individual alignment sites. For more information, refer to . |
SpliceAI | SpliceAI is the delta score of a variant that can also be interpreted as the probability of the variant being splice-altering. For more information, refer to . |
gnomAD | gnomAD consists of the following items: • Constraint metrics • LOEUF • misZ • pLi • pNull • pRec • synZ For more information, refer to . |