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Analysis of p.Ile203Met variant, CFTR gene, CF Transmembrane conductance Regulator protein (1480 residues)
Data provided and calculated by CYSMA must be considered as predictions. They are meant for educational purposes only and are provided with NO WARRANTY with respect to their biological reliability.
Allele frequency: |
Ortholog conservation: |
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Number of sequences | AAPI* | AAPIR** | Number of divergencies | Number of mutant M203 | Number of gaps | Conservation of I203 | Conservation - gap |
---|---|---|---|---|---|---|---|
50 | 80.72% | 84.34% | 1 show divergencies |
0 details |
0 details |
98.00% (49 / 50) | 98.00% (49 / 50) |
The wild-type residue I203 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs) The variant I203M has never been found among the CFTR orthologs
*AAPI: Alignment Average Percentage Identity
**AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 203). AAPIR appears in green if it is more than 10% compared to AAPI, in red if less than 10%. Click here for more details on the alignment.
CYSMA's visualizing modules for Ortholog conservation:
⬇ Download the region alignment (50 residues, Fasta format) ⬇ Download the CFTR phylogenic tree
Domain conservation: |
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The domain MSD1 of CF Transmembrane conductance Regulator has been shown to interact with:
The residue p.Ile203 belongs to the domain MSD1.
69 |
| 422 |
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MSD1 of CF Transmembrane conductance Regulator domain alignment including p.Ile203 residue.
Number of sequences | AAPID*** (from aa 69 to aa 422) |
AAPIR! | Number of divergencies | Number of mutant | Number of gaps | Conservation of I203 | Conservation - gap |
---|---|---|---|---|---|---|---|
429 | 17.13% | 13.88% | 304 show divergencies |
8 | 2 | 28.67% (123 / 429) | 28.81% (123 / 427) |
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 203). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
The wild-type residue I203 belongs to the MSD1 domain and is conserved at 28.67% among the MSD1 homologs (123 / 429 MSD1 homologs)
The variant I203M has been found among the MSD1 homologs with a non significant frequency: 1.86% (8 / 429 MSD1 homologs)
Divergencies show the amino acids which have been selected in the evolution. Residues present in more than 10% of the sequences are highlighted in blue. Please note that CYSMA does not consider splicing alterations. Refer to the Help page for more details.
CYSMA's visualizing modules for MSD1 domain conservation:
Refer to the Help page for more details.
Secondary structure analysis: |
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Residue p.Ile203 is predicted to belong to an α helice. Probability is 0.935.
Direct environment is as follow:
H | F | V | W | I203 | A | P | L | Q |
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Observed frequencies in α helices:
I: 0.99
M: 1.14
Mutant residue is more observed in this type of structure.
3D analysis: |
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Models provided and analysed by CYSMA must be considered as predictions, therefore be careful when interpreting the results. All efforts have been made to build structures of quality, however, they are provided with NO WARRANTY as to their accuracy with the real biological molecules studied.
Wild type and predicted mutant structures have been compared. You will find the results below.
PDB template | Sequence identity* | MolProbity bad rotamers | MolProbity Ramachandran outliers | MolProbity Ramachandran favored |
---|---|---|---|---|
5UAK | 99.8 % | 18/1313 - 1.37 % | 17/1478 - 1.15 % | 1360/1478 - 92.2 % |
Click on the MolProbity logo for complete details on the structure quality
CYSMA's modules to download the 3D structures:
CYSMA's 3D Automatic Annotation:
WARNING! The experimental 3D structure used for our predictions is the complete human CFTR structure which have been solved at a 3.7 Å resolution using cryo-electron microscopy (PDB: 5UAK; Liu et al. 2017). The overall resolution is fairly low so the CYSMA's 3D Automatic Annotation pipeline might have missed some important structural effects.
I203 | M203 |
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none | none |
I203 | M203 |
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4.71 Å between ILE 203 CG1 and TRP 202 CG 4.59 Å between ILE 203 CD1 and TRP 202 CG 4.87 Å between ILE 203 CB and TYR 89 CD1 4.83 Å between ILE 203 CG1 and TYR 89 CD1 4.37 Å between ILE 203 CG2 and TYR 89 CD1 3.65 Å between ILE 203 CD1 and TYR 89 CB 4.46 Å between ILE 203 CG1 and HIS 199 CE1 4.06 Å between ILE 203 CD1 and HIS 199 CE1 4.52 Å between ILE 203 CB and PHE 200 CB 4.73 Å between ILE 203 CG1 and PHE 200 CB 4.38 Å between ILE 203 CG2 and PHE 200 CD1 | 3.89 Å between MET 203 CE and LEU 88 CB 4.54 Å between MET 203 CB and TYR 89 CD1 4.59 Å between MET 203 CG and TYR 89 CB 4.20 Å between MET 203 CG and HIS 199 CE1 4.27 Å between MET 203 CE and HIS 199 CG 4.86 Å between MET 203 CE and PHE 200 CB |
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
I203 | M203 |
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none | none |
CYSMA's 3D visualizing module:
I203 (wild-type) | M203 (mutant) |
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JSmol Legends: The residue at the position 203 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å). Van der Waals contacts with the residue 203 are represented by dotted lines. Amino acids involved in H-bonds with the residue 203 are labelled in blue. Amino acids involved in steric clashes with the residue 203 are labelled in red.
Display JSmol complete legends
Display Molecular Modelling methods
Refer to the Help page for more details.Clinical significance: |
Patients data: CFTR-France |
Variant I203M might correspond to:
Name | NM_000492.3:c.609C>G |
Protein name | NP_000483.3:p.(Ile203Met) |
Genomic name | chr7:g.117175331C>G |
Class | unclassified |
Total number of patients | 1 |
CFTR-RD | 1
|
(CFTR-France for more details)
Additional resources: |
The variation is not reported in Uniprot.
CYSMA Report: |
CFTR orthologs conservation | The wild-type residue I203 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs)The variant I203M has never been found among the CFTR orthologs |
MSD1 homologs conservation | The wild-type residue I203 belongs to the MSD1 domain and is conserved at 28.67% among the MSD1 homologs (123 / 429 MSD1 homologs)
The variant I203M has been found among the MSD1 homologs with a non significant frequency: 1.86% (8 / 429 MSD1 homologs) |
Structural effects | The wild-type residue ILE is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is reduced in the mutant residue MET, which might slightly destabilize the region |
Allele frequency | The variant has not been reported in gnomAD |
Clinical significance | The variant I203M has been been described as not provided - no assertion provided - (ClinVar for more details) |
CFTR-France | The variant I203M might correspond to: NM_000492.3:c.609C>G, which is reported to be unclassified ( CFTR-France for more details) |
Additional resources | SIFT prediction: variant I203M is predicted to be damaging (score: 0.02) PPH2 prediction: variant I203M is predicted to be damaging (score: 1) |
CYSMA has completed its calculations; Execution time: 12 wallclock secs ( 8.39 usr 0.04 sys + 2.91 cusr 0.07 csys = 11.41 CPU)