Analyze variant(s)

Welcome to the Genetic Therapy Generator Toolkit, please specify one or more variants in a single HGVS description below:

Examples

The input must be an allele in HGVS format, describing variants on an Ensembl transcript.

Variant Explanation
ENST00000375549.8:c.100del Frameshift deletion in exon 2 of SHDH
NC_000023.11(NM_004006.3):c.2500del Frameshift deletion in exon 20 of DMD

Analysis results for ENST00000375549.8:c.149_150dup

GTGT analysis results for both the input variants and the wildtype version of the transcript. By definition, the Remaining percentage of the wildtype transcript is always 100%.

Input
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Variant description

DNA: ENST00000375549.8:c.149_150dup

RNA: ENST00000375549.8:r.149_150dup

Protein: ENST00000375549.8(ENSP00000364699):p.(Leu51ThrfsTer36)

Therapy description

The annotations based on the supplied input variants.

Transcript visualization
Visualization of the input variants and exons (with reading frames), generated with ExonViz. 12344c.149_150dup
Changed annotations
Annotation Remaining Basepairs Percentage
Exons 99.9% 1337/1339
Coding exons 44.6% 214/480
Mitochondrial ...: Mitochondrial matrix 22.2% 12/54
Mitochondrial ...: Mitochondrial intermembrane 20.0% 12/60
helix 18.8% 48/255
trans pep: Mitochondrion 89.9% 151/168
bind 0.0% 0/3
CybS 19.4% 60/309
Transmembrane: Helical 18.5% 36/195
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
bind: axial binding residue 100.0% 3/3
Wildtype
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Variant description

DNA: ENST00000375549.8:c.=

RNA: ENST00000375549.8:r.=

Protein: ENST00000375549.8(ENSP00000364699):p.(=)

Therapy description

These are the annotations as defined on the reference. They are always 100% by definition.

Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
Exons 100.0% 1339/1339
Coding exons 100.0% 480/480
Mitochondrial ...: Mitochondrial matrix 100.0% 54/54
Mitochondrial ...: Mitochondrial intermembrane 100.0% 60/60
helix 100.0% 255/255
trans pep: Mitochondrion 100.0% 168/168
bind: axial binding residue 100.0% 3/3
bind 100.0% 3/3
CybS 100.0% 309/309
Transmembrane: Helical 100.0% 195/195

Variant-modifying therapies

This section contains analysis results for therapies which directly modify or remove the specified input variants.

Skip exon 2
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Variant description

DNA: ENST00000375549.8:c.53_169del

RNA: ENST00000375549.8:r.53_169del

Protein: ENST00000375549.8(ENSP00000364699):p.(Leu19_Ser57del)

Therapy description

The annotations based on the supplied variants, in combination with skipping exon 2.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 91.3% 1222/1339
Coding exons 75.2% 361/480
Mitochondrial ...: Mitochondrial matrix 94.4% 51/54
trans pep: Mitochondrion 31.0% 52/168
CybS 99.0% 306/309
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
Mitochondrial ...: Mitochondrial intermembrane 100.0% 60/60
helix 100.0% 255/255
bind: axial binding residue 100.0% 3/3
bind 100.0% 3/3
Transmembrane: Helical 100.0% 195/195
Skip exons 2 and 3
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Variant description

DNA: ENST00000375549.8:c.53_314del

RNA: ENST00000375549.8:r.53_314del

Protein: ENST00000375549.8(ENSP00000364699):p.(Ala18GlyfsTer30)

Therapy description

The annotations based on the supplied variants, in combination with skipping exons 2 and 3.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 80.4% 1077/1339
Coding exons 13.3% 64/480
Mitochondrial ...: Mitochondrial matrix 11.1% 6/54
Mitochondrial ...: Mitochondrial intermembrane 5.0% 3/60
helix 2.4% 6/255
trans pep: Mitochondrion 30.4% 51/168
bind: axial binding residue 0.0% 0/3
bind 0.0% 0/3
CybS 3.9% 12/309
Transmembrane: Helical 1.5% 3/195

Other therapies

This section contains therapies which do not directly change any of the specified input variants.

Skip exon 3
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Variant description

DNA: ENST00000375549.8:c.[149_150delinsACAC;170_314del]

RNA: ENST00000375549.8:r.[149_150delinsACAC;170_314del]

Protein: ENST00000375549.8(ENSP00000364699):p.Leu51_Leu159delinsThrCysHisArgAlaThrIleGlyProTrpThrSerCysTyr

Therapy description

The annotations based on the supplied variants, in combination with skipping exon 3.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 89.0% 1192/1339
Coding exons 34.8% 167/480
Mitochondrial ...: Mitochondrial matrix 5.6% 3/54
Mitochondrial ...: Mitochondrial intermembrane 0.0% 0/60
helix 5.9% 15/255
trans pep: Mitochondrion 89.9% 151/168
bind: axial binding residue 0.0% 0/3
bind 0.0% 0/3
CybS 4.9% 15/309
Transmembrane: Helical 6.2% 12/195
External resources
OMIM_1

This is a description of the omim_1 database
LOVD

This is a description of the lovd database
GTEX

This is a description of the gtex database
UNIPROT

This is a description of the uniprot database
DECIPHER

This is a description of the decipher database
CLINVAR

This is a description of the clinvar database
HGNC

This is a description of the hgnc database
UCSC

This is a description of the ucsc database
GNOMAD

This is a description of the gnomad database
STRINGDB

This is a description of the stringdb database
Export report

Here will be an option to export the report, either as a stand alone html page or a PDF document

Documentation
Introduction

The Genetic Therapy Generator Toolkit helps users determine whether a given variant (or set of variants) can be corrected with a genetic therapy. Rather than relying on explicit guidelines about which kinds of variants can be treated, GTGT simulates the effect of every possible therapy and ranks the therapies based on how many of the transcript features are restored.

Because of this unique approach, GTGT can identify possible therapies when it appears none are available, for example by skipping upstream or downstream exons to restore the reading frame, or by skipping adjacent exons (experimental).

Interpreting results

The first two entries on the results page will always be the analysis of the Wildtype and Input versions of the transcript. Each entry contains the name, HGVS notation and short description of the therapy. The most important section is the Annotation overview, which lists the percentage of each feature of the transcript that remains after the mutations (and therapy) have been applied. The Exons feature refers to all bases that make up the exon. When GTGT skips an exon, the bases of the exon will be removed from the Exons feature, which can be seen from the percentage and the remaining basepairs. The Coding exons refer to the bases that make up the coding sequence of the transcript. Changes in the Coding exons take the actual predicted protein changes in the transcript into account. For example, in the case of a frameshift variant all bases after the frameshift will be removed from the Coding exons feature, but not from the Exons.

The extended documentation for this tool can be found on https://gtgt.readthedocs.io.

Development

The Genetic Therapy Generator Toolkit has been developed by the Dutch Center for RNA Therapeutics, who have committed to continue to fund the development of GTGT until at least June 2027.

GTGT can be installed locally via PyPi, or you can install the development version from Github. We welcome contributions, bug reports and other feedback on GitHub or via an email to DCRT@LUMC.nl.

GTGT is free to use and redistribute under the conditions of the GNU Affero General Public License v3.0.

Disclaimer

Copyright© 2023 LUMC https://www.lumc.nl

This program is free software: you can redistribute it and/or modify it under the terms of the GNU Affero General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version.

This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU Affero General Public License for more details.

By accessing and using the program in any manner (including copying, modifying or redistributing the program), you accept and agree to the applicability of the GNU Affero General Public License. You can find and read this license on GNU Affero General Public License - GNU Project - Free Software Foundation.