SNVs and InDels

Charlene Son-Rigby -

This article describes all data columns in the Variants Table and all options of the Filters Menu for small variants, SNVs and InDels. This table is used to display small variants in Clinical Reporter in the Variant Selection and Variant Interpretation pages and in Variant Miner.

Actions other than filtering are module specific and described in the articles for the page using the table.

Variants Table

The availability of the data columns varies by module and test and any restrictions are indicated below.

The default sort order of the Variants table is by Position except for VAAST test which are sorted by VAAST Rank or Phevor Rank if Phevor has been run. Unless otherwise noted the columns of the Variants table are sortable by clicking on the column header. The current sort order is indicated by gray shading in the header.

Checkbox
Click the checkbox to the left of a variant to select or unselect it. To select or unselect all variants visible on the current page click on the checkbox in the table header.
Not available in all views. Not sortable.
Review Priority
The Review Priority column provides a visual prioritization of variants based on three data elements: ClinVar Classification, Allele Frequencies and Effect. Mousing over the Review Priority symbols provides a key to the color coding of the data elements. See Appendix 3 for more details.
Click on the column header to sort all variants by Review Priority with pathogenic, rare, and most severe effect at the top. Click again to invert the sort order.
Reports generated from Opal Pipeline 4.3 and below use the Variant Classification (previously Predicted Class) column. See Appendix 7 for more details.
Gene
The official HGNC (Hugo Gene Nomenclature Committee) symbol for the gene. Click on the symbol to open the Gene Detail display.
Position dbSNP
Chromosome and start position of the variant. Click on the hyperlink to view this position in the UCSC genome browser.
Click on the column header to sort all variants alphanumerically by chromosome/position.
Change
Reference and variant allele sequence for this variant. In addition, the HGVS (Human Genome Variation Society) notation for the nucleotide and protein change (if any) for a representative transcript.
If the BAM Browser Link is configured for the workspace and IGV installed and open, clicking on Change moves the IGV application view to this position.
If the Alamut Link is configured for the workspace, clicking on the AV link in the top right corner to link out to Alamut.
Contact support@fabricgenomics.com to enable IGV and Alamut link outs.
Not sortable.
Effect
Impact of the variant on the gene and transcripts predicted by VEP (Variant Effect Predictor - Ensembl), e.g. missense, synonymousstop gained/lost, intron, frameshift, splice acceptor/donor. If multiple transcripts exist for the gene the most severe impact is displayed. Clicking on Effect opens the Variant Consequences display.
Additionally the "splice site impact" text will be color coded for the NNsplice prediction of disruption or creation of a splice sites:
splice site impact (reference score - variant score) > 0.5
splice site impact (reference score - variant score) > 0.25
Click on the column header to sort all variants by Effect with the most deleterious at the top. Click again to invert sort order.
Zygosity
A graphical, color coded display of the genotype of the variant, homozygous or heterozygous. The variant allele is represented by a full circle. The color coding indicates whether the variant passed (black circles) or failed (red circles) the VCF file FILTER.
For tests including family members a Zygosity column is added for each member. If the variant is not present in a family member the field is empty.
In Clinical Reporter, for variants that match the De Novo mode of Inheritance in Trio and Quad tests homozygous reference calls in the family members are displayed as two open circles if the VCF files contain reference calls at the variant position. No-calls in the family members are represented as dashes.
The Zygosity column is sortable whereas the Zygosity column for family members is not sortable.
Quality GQ Coverage
The fields in this column contain three different quality metrics that are extracted from the VCF file, Quality, GQ and Coverage. Missing quality metrics are represented by '-'.
Quality
The QUAL value from the VCF file is a Phred-like score measuring the confidence that the position is not homozygous reference.
Clicking on the column header will sort the column by Quality.
GQ
The FORMAT tag GQ (Genotype Quality) is a Phred-like score measuring the confidence in the called genotype. The GQ value is color coded:
GQ >= 20
GQ < 20
Coverage
The read coverage at that position in the format Total:Reference:Variant. For heterozygous variants, coverage is color coded to highlight Allelic Balance:
variant allele fraction 45–55%
variant allele fraction 30-44% or 56-70%
variant allele fraction <30% or >70%
These thresholds are based on analysis of allele balance and false positives (Pirooznia et al., 2014).
For tests including family members a Quality GQ Coverage column is added for each member. If the variant is not present in a family member the field is empty.
1KG AF  EVS AF  ExAC AF
Frequencies from 1000 Genomes Project, Exome Variant Server and ExAC. Click on the hyperlinks to access the ethnic subpopulation frequencies and genotype counts.
A dash indicates the variant was not observed in that database. If no frequencies are available in all 3 databases a Beacon symbol is shown instead. Click on the beacon to search the Beacon Network (Global Alliance for Genomics & Health) for this variant.
Not sortable.
Omicia Score
Proprietary impact assessment score that provides a rational aggregation of other variant scoring algorithms (Coonrod et al, 2013).  The color coded values range from 0 to 1, with higher values indicating more likely deleteriousness:
Omicia Score <= 0.5
>0.5 < Omicia Score <= 0.85
Omicia Score > 0.85
Clicking on the Omicia score opens a displays with all individual scores and descriptions (see Appendix 2 for more information).
Click on the column header to sort all variants by the Omicia Score.
The four colored squares underneath the Omicia score denote the individual evaluations of the underlying component scores, mousing over them shows the sources, Mutation Taster, PolyPhen 2, SIFT and PhyoP Vertebrate. The range is red-yellow-green-gray, with red deleterious, green benign and gray no information. This provides insight into the concordance of the underlying scores. In Clinical Reporter, these scores can also be displayed as additional columns in the table.
VVP CADD
This column provides 2 other aggregate scores, VVP and CADD.
VVP
The VAAST Variant Prioritization (VVP) score applies the VAAST algorithm at the variant level. VAAST takes predicted protein impact, conservation and allele frequency into consideration in its deleteriousness assessment. VVP provides normalized scores for variants in genes, enabling direct comparison of variants in conserved and polymorphic genes. VVP scores are provided for coding, non-coding regions, and intergenic variant categories, allowing comparison of these types of variants across genes.
VVP < 50
50 <= VVP < 70
VVP >= 70
Click on the column header to sort by VVP score.
CADD
The CADD score combines information from 63 different annotations including PhastCons, GERP, PhyloP, SIFT and PolyPhen, using a support vector machine classifier (Kircher et al, 2013). It measures deleteriousness by using observed variant frequency as the basis for its calculation. The C score ranges from 1 to 99, with a higher score indicating greater deleteriousness. Values >= 10 are predicted to be the 10% most deleterious substitutions, >= 20 indicate the 1% most deleterious.
CADD < 5
5 <= CADD < 20
CADD >= 20
Evidence 
Literature evidence gathered from ClinVar, OMIM, COSMIC, Locus Specific Databases and GWAS. For OMIM, only variants annotated as Allelic Variants show Evidence links. Click on the icons to display detailed information on the evidence.  Not sortable.
Class
Only in Clinical Reporter.
This column indicates the Clinical Classification assigned to the variant in this report from Variant ScoringPathogenic, Likely Pathogenic, Uncertain Significance, Likely Benign, and Benign, as well as any customer defined classifications. For more information on custom classifications please contact Customer Support at support@fabricgenomics.com.
The condition associated with this classification is displayed in parentheses.
Click on the column header to sort by pathogenicity.
VAAST Rank
Only for VAAST tests/reports.
VAAST is Fabric Genomics' advanced algorithm for ranking disease-causing variants and genes. Reports that use VAAST analysis are sorted by VAAST rank by default. Mousing over the VAAST Rank value will display the VAAST p-value, variant score and gene score.
More information on VAAST is provided in the Advanced Genome Analysis Using VAAST section.
VAAST V-Score
Only for VAAST reports in Variant Miner.
The VAAST V-Score or Variant Score is a 'burden test' score based on the nature of the amino-acid change induced by the variant (if any) and the relative enrichment of the frequency in the affected versus unaffected individuals. Higher scores are more damaging.
VAAST G-Score
Only for VAAST reports in Variant Miner.
The VAAST G-Score or Gene Score is the sum of the Variant Scores for every variant in the gene. The larger the VAAST Gene Score, the more likely that gene is to be damaged in the affected individuals.
The VAAST p-value, displayed underneath the VAAST Gene Score, is the probability of observing that Gene Score by random chance given the dataset. Some genes naturally contain many rare, weakly damaging alleles; thus a high VAAST gene-score is not necessary unexpected. When prioritizing candidate genes focus on those with a high VAAST score and low VAAST p-value.
Phevor Gene Rank
Only for VAAST tests in Clinical Reporter.
Phevor works in conjunction with VAAST and ranks disease gene candidates using phenotype information.
VAAST Inheritance Mode
Only for VAAST tests/reports. The inheritance mode used by the VAAST algorithm rules.
When "All" is selected from the Report Filters Inheritance dropdown menu, the VAAST Inheritance Mode column is displayed by default in the variant table, and indicates under which inheritance model the variant was scored by VAAST. If a variant is ranked for multiple inheritance modes, it will be displayed multiple times in the variant table. If the variant was not ranked by VAAST this field remains empty.
Source
Only in Clinical Reporter.
This column is specific to non-panel tests and indicates how a variant was added to the report. Possible values are:
VAAST
The variant was added by the VAAST algorithm.
FLEX
The variant is added because it is a coding variant that matches the inheritance pattern. Only for Trio and Quad tests.
Manually Added
The variant was added manually through Add Variants.
Scoring Status
Only in Clinical Reporter.
This column indicates the Scoring Status for a variant. For a variant that has never been scored before this field will be empty.
Previously Scored
The variant was classified and finalized as scored in another patient report in this workspace, and is in your lab's Previously Scored database.
Scoring
Evidence review and scoring process has started but the classification has not been finalized yet.
Scored
The variant has been finalized as Scored for this report, see Scoring Variants for details on the scoring process.
Confirmation Status
Only in Clinical Reporter.
The dropdown menu for each variant enables tracking of variant confirmation with alternative technologies:
To Be Confirmed
Choose this option to mark a variant for confirmation. Only variants marked with this confirmation status will be exported with the Export Variants To Be Confirmed option from the Actions menu on the Clinical Reports page.
Confirmed
Indicates successful confirmation of the variant for this sample.
Failed Confirmation
Indicates the variant was not confirmed for this sample.
No Status
Default if now other status is selected.
Up to 4 custom Confirmation Statuses can be defined. For more information please contact Customer Support at support@fabricgenomics.com.
Report Section
Only in Clinical Reporter.
Here the section of the Clinical Report in which a scored variant will be reported in is specified as either Primary Findings, Secondary Findings or Not Reported.
Latest Classification (Date Classified) Confirmation Status
For previously scored variants the last classification, the date when classified and, if available, the Confirmation Status is displayed. If that classification is not finalized Scoring in Progress is shown instead.

Filters Menu

The filtering options in the Filters menu affect the display of variants only on the current page. The options available vary by module and test, and depend on the columns in the Variants table. By default Exclude: Filter failures is preselected for all tests, as well as Exclude: Non-coding GenesRequire: Protein Changing and Report Filters - Inheritance - Recessive for non-panel tests. The Variant Interpretation view in Clinical Reporter has no default filters set.

Filtering Protocols

The Apply Protocol dropdown menu lets you filter the variants by any protocol defined in Filtering Protocols. A Filtering Protocol enables convenient one-click application of multiple filters from the Filters menu and will override all other filter settings.

Report Filters

Only in Clinical Reporter. This menu provides options to filter the variants by their status in this report:

Scoring Status
Dropdown menu to filter the variants by the Scoring Statuses AllScoringScoredPreviously Scored, or No Status.
Class
Dropdown menu to filter variants by their clinical classification for this sample. In addition to the default classes AllPathogenic, Likely Pathogenic, Uncertain Significance, Likely Benign, Benign, and No Class (not classified yet), any customer-defined classes can also be filtered on.
Confirmation Status
Dropdown menu to filter variants by their confirmation status. In addition to the default options AllTo Be Confirmed, Confirmed, Failed Confirmation, No Status, or Any with Status, any customer-defined Confirmation Statuses are available as well.
Latest Classification
Dropdown menu to filter variants by the most recent clinical classification for this sample in your lab's workspace. In addition to the default classes AllPathogenic, Likely Pathogenic, Uncertain Significance, Likely Benign, Benign, and Not Previously Classified, any customer-defined classes can be filtered on.
Inheritance 
Dropdown menu to filter variants by inheritance mode. Depending on the test, the options are Recessive, Dominant, X-linked, De Novo, or All. Not available for Panel tests in Clinical Reporter.
In Variant Interpretation Page
Only available for Solo and Family Reports, in the Variant Selection page. Select variants that have already been short-listed to the Variant Interpretation page, or variants that have not been added.

Gene Filters

Allows you to select variants that match any single filter specified, or require that they match all of the specified filters.

Gene Symbol
Enter gene symbol(s) to display only variants in those genes.
Gene Panel
Select a Gene Panel built in Panel Builder from the dropdown menu to include variants found in genes from the gene panel.
Gene Sets
Select a Gene Set from the dropdown menu to include variants found in genes from the gene set. 
Genes Added from Chromosomal Regions
This checkbox option is available only for Panel tests if the panel used contains genes that were added by specifying chromosomal regions in Add Genes to Panel.

Zygosity

For Solo, Family and Panel Trio tests, zygosity filtering is available for each family member. Each of the dropdown menus has the options Any, Heterozygous, or Homozygous.

RSID

Search for variants by rsID(s).

Location

Filter based on chromosome and location within the chromosome.  If your sample contains regions of homozygosity (regions that are at least 1 MB in size with a density of homozygous variants of at least 75% - see the table in the ROH Report for your sample), you can also specify whether you want to filter for variants in regions of homozygosity that are greater than 5MB, 3MB, or 1MB.

Quality

This menu provides several filtering options for quality metrics, which allow you to focus on higher quality variants by raising the lower bound or reducing highly redundant reads that may indicate a missasembly. The filters are presented as text entry boxes to set minimum and maximum cutoffs. 
 
The Match option allows you to select variants that match any single filter specified, or require that they match all of the specified filters.

Coverage:   min and max values encountered in VCF file
Quality:   min and max values encountered in VCF file
Genotype Quality:   min and max values encountered in VCF file
Allele Balance: For heterozygous variants, show only those with an allelic balance Between 0.45-0.55, Between 0.30-0.70 or Any allelic balance.

Evidence

ClinVar Classification

These checkbox options filter variants based on their classification records in ClinVar. Records are considered if the record matches the variant allele or matches the variant amino acid. If none of these options are selected variants are shown regardless of their ClinVar records.

Pathogenic
Show variants with exclusively 'pathogenic' records in ClinVar (red ClinVar dot in Review Priority).
Likely Pathogenic
Show variants with a combination of different records including at least one 'likely pathogenic' or 'pathogenic' record (red ClinVar dot in Review Priority).
Uncertain Significance
Show variants with exclusively 'uncertain significance' records or variants with at least one 'conflicting interpretations of pathogenicity' but no 'likely pathogenic' or 'pathogenic' (yellow ClinVar dot in Review Priority).
Likely Benign
Show variants with a combination of records including at least one 'likely benign' or 'benign' record (green ClinVar dot in Review Priority).
Benign
Show variants with exclusively 'benign' records (green ClinVar dot in Review Priority).
Associated
Show variants that have at least one record with the clinical significance of 'association', 'confers sensitivity', 'drug response', 'protective' or 'risk factor', but no record with 'pathogenic', 'likely pathogenic', 'likely benign' or 'benign' records (yellow ClinVar dot in Review Priority).
In ClinVar, No Class
Show variants that are included in ClinVar but have only records with a clinical significance of 'not provided' (gray ClinVar dot in Review Priority).
Supporting Evidence

Show only variants that have supporting evidence in OMIM and/or ClinVar, or show only variants that have Any type of supporting evidence (ClinVar, OMIM, GWAS, etc.).

Allele Frequency

The Match option allows you to select variants that match any single filter specified, or require that they match all of the specified filters.

EVS AF:   0 - 100
ExAC AF:   0 - 100
1KG AF:   0 - 100

Impact Scores

The Match option allows you to select variants that match any single filter specified, or require that they match all of the specified filters. 

Omicia Score:   0 - 1
Sift Score:   0 - 1
VVP Score:   0 - 100
CADD Score:   0 - 99

Variant Effect

Variant Type
Select to show only Protein Changing variants and/or variants with Regulatory consequences. If both options are selected variants have to meet both requirements to pass the filter. Protein Changing variants can be further specified by selecting one or multiple variant types, e.g. Missense, Splice Regions, etc. The Regulatory consequences are generated from Ensembl annotations.
Gene Models
Show only variants overlapping CCDS and/or RefSeq gene models.

Exclude

The Exclude menu provides filtering option to exclude variants from the report.

Genome Region
Exclude variants in Introns and/or Intergenic Regions.
Variant Type
Exclude variants with dbSNP Hits to show only novel variants.
VCF Filters
Filter failures
Exclude variants that have a value other than '.' (missing) or 'PASS' in the FILTER field of the VCF file.
Filter unspecified
Exclude variants that have the value '.' (missing) in the FILTER field of the VCF file.

Gene Type

Exclude variants in Polymorphic Genes and/or Non-coding Genes.

Exclude Gene Sets

Select a Gene Set from the Add Gene Set dropdown menu to exclude variants found in genes from the gene set. Only gene sets categorized as Exclude Sets in Gene Sets are available in this menu.

Unique Variants

This option is only available in Variant Miner for a Variant Report and filters the variants to show only variants unique to this sample when compared with other genomes. Click the Select Genomes button to open the Find Unique Variants dialog and select the comparison genomes.

Shared Variants

This option is only available in Variant Miner for a Variant Report and filters the variants to show only variants in common with other genomes. Click the Select Genomes button to open the Find Shared Variants dialog and select the comparison genomes.

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