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 ENST00000636147.2:c.461_677del

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: ENST00000636147.2:c.461_677del

RNA: ENST00000636147.2:r.461_677del

Protein: ENST00000636147.2(ENSP00000490105):p.(Gly154AlafsTer29)

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. 12345678910111213141516c.461_677del
Changed annotations
Annotation Remaining Basepairs Percentage
Exons 87.1% 1468/1685
Coding exons 38.0% 501/1317
Lumenal: Lumenal 56.7% 216/381
propep: Removed in mature form 33.3% 3/9
Lysosomal targ...: Lysosomal targeting motif 0.0% 0/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 0.0% 0/6
modif: Cysteine methyl ester 0.0% 0/3
Lipidation: S-farnesyl cysteine 0.0% 0/3
glyco: N-linked (GlcNAc...) asparagine 66.7% 6/9
BTS 37.9% 495/1305
Cytoplasmic: Cytoplasmic 25.9% 144/555
Transmembrane: Helical 36.5% 138/378
Disordered: Disordered 47.4% 81/171
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
biased: Basic and acidic residues 100.0% 45/45
phos: Phosphoserine 100.0% 6/6
Wildtype
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Variant description

DNA: ENST00000636147.2:c.=

RNA: ENST00000636147.2:r.=

Protein: ENST00000636147.2(ENSP00000490105):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% 1685/1685
Coding exons 100.0% 1317/1317
Lumenal: Lumenal 100.0% 381/381
propep: Removed in mature form 100.0% 9/9
Lysosomal targ...: Lysosomal targeting motif 100.0% 42/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 100.0% 6/6
biased: Basic and acidic residues 100.0% 45/45
modif: Cysteine methyl ester 100.0% 3/3
Lipidation: S-farnesyl cysteine 100.0% 3/3
glyco: N-linked (GlcNAc...) asparagine 100.0% 9/9
phos: Phosphoserine 100.0% 6/6
BTS 100.0% 1305/1305
Cytoplasmic: Cytoplasmic 100.0% 555/555
Transmembrane: Helical 100.0% 378/378
Disordered: Disordered 100.0% 171/171

Variant-modifying therapies

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

Other therapies

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

Skip exon 7
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Variant description

DNA: ENST00000636147.2:c.[375_460del;461_677del]

RNA: ENST00000636147.2:r.[375_460del;461_677del]

Protein: ENST00000636147.2(ENSP00000490105):p.(Pro126_Ser226del)

Therapy description

The annotations based on the supplied variants, in combination with skipping exon 7.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 82.0% 1382/1685
Coding exons 76.9% 1013/1317
Lumenal: Lumenal 90.3% 344/381
BTS 76.7% 1001/1305
Cytoplasmic: Cytoplasmic 85.9% 477/555
Transmembrane: Helical 50.0% 189/378
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
propep: Removed in mature form 100.0% 9/9
Lysosomal targ...: Lysosomal targeting motif 100.0% 42/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 100.0% 6/6
biased: Basic and acidic residues 100.0% 45/45
modif: Cysteine methyl ester 100.0% 3/3
Lipidation: S-farnesyl cysteine 100.0% 3/3
glyco: N-linked (GlcNAc...) asparagine 100.0% 9/9
phos: Phosphoserine 100.0% 6/6
Disordered: Disordered 100.0% 171/171
Skip exon 6
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Variant description

DNA: ENST00000636147.2:c.[295_374del;461_677del]

RNA: ENST00000636147.2:r.[295_374del;461_677del]

Protein: ENST00000636147.2(ENSP00000490105):p.(Ala99_Ser226delinsProProGlySerArgGlnTrpAspLeuCysCysTrpLysLeuArgProGlyCysLeuPheSerPheCysGlyAspGlnProValCys)

Therapy description

The annotations based on the supplied variants, in combination with skipping exon 6.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 82.4% 1388/1685
Coding exons 72.1% 949/1317
Lumenal: Lumenal 70.3% 268/381
BTS 71.8% 937/1305
Cytoplasmic: Cytoplasmic 86.5% 480/555
Transmembrane: Helical 52.4% 198/378
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
propep: Removed in mature form 100.0% 9/9
Lysosomal targ...: Lysosomal targeting motif 100.0% 42/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 100.0% 6/6
biased: Basic and acidic residues 100.0% 45/45
modif: Cysteine methyl ester 100.0% 3/3
Lipidation: S-farnesyl cysteine 100.0% 3/3
glyco: N-linked (GlcNAc...) asparagine 100.0% 9/9
phos: Phosphoserine 100.0% 6/6
Disordered: Disordered 100.0% 171/171
Skip exons 5 and 6
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Variant description

DNA: ENST00000636147.2:c.[223_374del;461_677del]

RNA: ENST00000636147.2:r.[223_374del;461_677del]

Protein: ENST00000636147.2(ENSP00000490105):p.(Val75_Ser226delinsProProGlySerArgGlnTrpAspLeuCysCysTrpLysLeuArgProGlyCysLeuPheSerPheCysGlyAspGlnProValCys)

Therapy description

The annotations based on the supplied variants, in combination with skipping exons 5 and 6.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 78.1% 1316/1685
Coding exons 66.6% 877/1317
Lumenal: Lumenal 50.4% 192/381
glyco: N-linked (GlcNAc...) asparagine 66.7% 6/9
BTS 66.3% 865/1305
Cytoplasmic: Cytoplasmic 85.9% 477/555
Transmembrane: Helical 54.2% 205/378
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
propep: Removed in mature form 100.0% 9/9
Lysosomal targ...: Lysosomal targeting motif 100.0% 42/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 100.0% 6/6
biased: Basic and acidic residues 100.0% 45/45
modif: Cysteine methyl ester 100.0% 3/3
Lipidation: S-farnesyl cysteine 100.0% 3/3
phos: Phosphoserine 100.0% 6/6
Disordered: Disordered 100.0% 171/171
Skip exon 10
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Variant description

DNA: ENST00000636147.2:c.[461_677del;678_790del]

RNA: ENST00000636147.2:r.[461_677del;678_790del]

Protein: ENST00000636147.2(ENSP00000490105):p.(Val155_Gly264del)

Therapy description

The annotations based on the supplied variants, in combination with skipping exon 10.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 80.4% 1355/1685
Coding exons 74.8% 985/1317
Lumenal: Lumenal 92.1% 351/381
Lysosomal targ...: Lysosomal targeting motif 78.6% 33/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 0.0% 0/6
BTS 74.6% 973/1305
Cytoplasmic: Cytoplasmic 67.0% 372/555
Transmembrane: Helical 68.5% 259/378
Disordered: Disordered 50.9% 87/171
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
propep: Removed in mature form 100.0% 9/9
biased: Basic and acidic residues 100.0% 45/45
modif: Cysteine methyl ester 100.0% 3/3
Lipidation: S-farnesyl cysteine 100.0% 3/3
glyco: N-linked (GlcNAc...) asparagine 100.0% 9/9
phos: Phosphoserine 100.0% 6/6
Skip exons 10 and 11
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Variant description

DNA: ENST00000636147.2:c.[461_677del;678_837del]

RNA: ENST00000636147.2:r.[461_677del;678_837del]

Protein: ENST00000636147.2(ENSP00000490105):p.Val155_Ser438delinsSerAlaValValHisCysSerLeuGlyArgSerLeuLeuCysArgValPheHis

Therapy description

The annotations based on the supplied variants, in combination with skipping exons 10 and 11.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 77.6% 1308/1685
Coding exons 36.3% 478/1317
Lumenal: Lumenal 55.9% 213/381
propep: Removed in mature form 0.0% 0/9
Lysosomal targ...: Lysosomal targeting motif 0.0% 0/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 0.0% 0/6
modif: Cysteine methyl ester 0.0% 0/3
Lipidation: S-farnesyl cysteine 0.0% 0/3
glyco: N-linked (GlcNAc...) asparagine 66.7% 6/9
BTS 36.4% 475/1305
Cytoplasmic: Cytoplasmic 22.2% 123/555
Transmembrane: Helical 36.8% 139/378
Disordered: Disordered 43.9% 75/171
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
biased: Basic and acidic residues 100.0% 45/45
phos: Phosphoserine 100.0% 6/6
Skip exon 4
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Variant description

DNA: ENST00000636147.2:c.[126_222del;461_677del]

RNA: ENST00000636147.2:r.[126_222del;461_677del]

Protein: ENST00000636147.2(ENSP00000490105):p.Leu43_Leu437delinsTrpThrGlnAlaGlnArgArgSerProThrThrAlaHisHisAspLeuThrAlaThrLeuSerLeuArgLeuLeuCysSerTrpArgThrSerSerProHisSerSerSerAsnCysTrpLeuLeuLeuAlaPheThrCysCysProThrAlaProGlyPheSerSerValGlyPheValLeuLeuGluAlaSerSerTrpLeuProPheLeuIleLeuTrpGlyProAlaCysValLeuPheLeuValAlaHisIle

Therapy description

The annotations based on the supplied variants, in combination with skipping exon 4.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 81.4% 1371/1685
Coding exons 22.0% 290/1317
Lumenal: Lumenal 18.9% 72/381
propep: Removed in mature form 33.3% 3/9
Lysosomal targ...: Lysosomal targeting motif 0.0% 0/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 0.0% 0/6
modif: Cysteine methyl ester 0.0% 0/3
Lipidation: S-farnesyl cysteine 0.0% 0/3
glyco: N-linked (GlcNAc...) asparagine 0.0% 0/9
BTS 21.8% 284/1305
Cytoplasmic: Cytoplasmic 29.2% 162/555
Transmembrane: Helical 14.0% 53/378
Disordered: Disordered 56.1% 96/171
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
biased: Basic and acidic residues 100.0% 45/45
phos: Phosphoserine 100.0% 6/6
Skip exons 4 and 5
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Variant description

DNA: ENST00000636147.2:c.[126_294del;461_677del]

RNA: ENST00000636147.2:r.[126_294del;461_677del]

Protein: ENST00000636147.2(ENSP00000490105):p.Leu44_Leu437delinsCysSerTrpArgThrSerSerProHisSerSerSerAsnCysTrpLeuLeuLeuAlaPheThrCysCysProThrAlaProGlyPheSerSerValGlyPheValLeuLeuGluAlaSerSerTrpLeuProPheLeuIleLeuTrpGlyProAlaCysValLeuPheLeuValAlaHisIle

Therapy description

The annotations based on the supplied variants, in combination with skipping exons 4 and 5.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 77.1% 1299/1685
Coding exons 17.2% 227/1317
Lumenal: Lumenal 7.1% 27/381
propep: Removed in mature form 33.3% 3/9
Lysosomal targ...: Lysosomal targeting motif 0.0% 0/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 0.0% 0/6
modif: Cysteine methyl ester 0.0% 0/3
Lipidation: S-farnesyl cysteine 0.0% 0/3
glyco: N-linked (GlcNAc...) asparagine 0.0% 0/9
BTS 16.9% 221/1305
Cytoplasmic: Cytoplasmic 28.1% 156/555
Transmembrane: Helical 10.8% 41/378
Disordered: Disordered 47.4% 81/171
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
biased: Basic and acidic residues 100.0% 45/45
phos: Phosphoserine 100.0% 6/6
Skip exons 3 and 4
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Variant description

DNA: ENST00000636147.2:c.[47_222del;461_677del]

RNA: ENST00000636147.2:r.[47_222del;461_677del]

Protein: ENST00000636147.2(ENSP00000490105):p.(Glu17_Ser438delinsGlyProArgProAsnAlaAspProProGlnGlnLeuIleThrIle)

Therapy description

The annotations based on the supplied variants, in combination with skipping exons 3 and 4.

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 76.7% 1292/1685
Coding exons 4.6% 61/1317
Lumenal: Lumenal 1.6% 6/381
propep: Removed in mature form 0.0% 0/9
Lysosomal targ...: Lysosomal targeting motif 0.0% 0/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 50.0% 3/6
biased: Basic and acidic residues 42.2% 19/45
modif: Cysteine methyl ester 0.0% 0/3
Lipidation: S-farnesyl cysteine 0.0% 0/3
glyco: N-linked (GlcNAc...) asparagine 0.0% 0/9
BTS 4.4% 58/1305
Cytoplasmic: Cytoplasmic 9.4% 52/555
Transmembrane: Helical 0.0% 0/378
Disordered: Disordered 28.7% 49/171
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
phos: Phosphoserine 100.0% 6/6
Skip exon 3
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Variant description

DNA: ENST00000636147.2:c.[47_125del;461_677del]

RNA: ENST00000636147.2:r.[47_125del;461_677del]

Protein: ENST00000636147.2(ENSP00000490105):p.Glu17_Ser438delinsCysTrpAlaPheAlaThrThrSerLeuMetTrp

Therapy description

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

Changed annotations
Annotation Remaining Basepairs Percentage
Exons 82.4% 1389/1685
Coding exons 5.8% 76/1317
Lumenal: Lumenal 3.1% 12/381
propep: Removed in mature form 0.0% 0/9
Lysosomal targ...: Lysosomal targeting motif 0.0% 0/42
Lysosomal targ...: Lysosomal targeting motif. Required for AP1G1, AP2A2 and AP3D1 interaction 0.0% 0/6
biased: Basic and acidic residues 42.2% 19/45
modif: Cysteine methyl ester 0.0% 0/3
Lipidation: S-farnesyl cysteine 0.0% 0/3
glyco: N-linked (GlcNAc...) asparagine 0.0% 0/9
BTS 5.6% 73/1305
Cytoplasmic: Cytoplasmic 10.5% 58/555
Transmembrane: Helical 0.8% 3/378
Disordered: Disordered 28.7% 49/171
Unchanged annotations arrow_drop_down
Annotation Remaining Basepairs Percentage
phos: Phosphoserine 100.0% 6/6
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.