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Analysis of p.Phe587Ile 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 I587 | Number of gaps | Conservation of F587 | Conservation - gap |
---|---|---|---|---|---|---|---|
50 | 80.72% | 90.11% | 1 show divergencies |
0 details |
0 details |
98.00% (49 / 50) | 98.00% (49 / 50) |
The wild-type residue F587 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs) The variant F587I 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 587). 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 NBD1 of CF Transmembrane conductance Regulator has been shown to interact with:
The residue p.Phe587 belongs to the domain NBD1.
423 |
| 649 |
|
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NBD1 of CF Transmembrane conductance Regulator domain alignment including p.Phe587 residue.
Number of sequences | AAPID*** (from aa 423 to aa 649) |
AAPIR! | Number of divergencies | Number of mutant | Number of gaps | Conservation of F587 | Conservation - gap |
---|---|---|---|---|---|---|---|
3982 | 26.61% | 16.56% | 3486 show divergencies |
193 | 3 | 12.38% (493 / 3982) | 12.39% (493 / 3979) |
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 587). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
The wild-type residue F587 belongs to the NBD1 domain and is conserved at 12.38% among the NBD1 homologs (493 / 3982 NBD1 homologs)
The variant F587I has been found among the NBD1 homologs with a non significant frequency: 4.85% (193 / 3982 NBD1 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 NBD1 domain conservation:
Refer to the Help page for more details.
Secondary structure analysis: |
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Residue p.Phe587 is predicted to belong to an α helice. Probability is 0.988.
Direct environment is as follow:
E | K | E | I | F587 | E | S | C | V |
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Observed frequencies in α helices:
F: 0.97
I: 0.99
The two residues are found equivalent 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.
F587 | I587 |
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none | none |
F587 | I587 |
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3.83 Å between PHE 587 CE1 and LEU 602 CD2 3.92 Å between PHE 587 CZ and LEU 602 CD2 4.89 Å between PHE 587 CD2 and HIS 609 CB 4.34 Å between PHE 587 CE1 and HIS 609 CG 3.95 Å between PHE 587 CE2 and HIS 609 CG 3.43 Å between PHE 587 CZ and HIS 609 CG 4.79 Å between PHE 587 CG and VAL 591 CG2 4.10 Å between PHE 587 CD1 and VAL 591 CG2 3.98 Å between PHE 587 CE1 and VAL 591 CG2 4.59 Å between PHE 587 CZ and VAL 591 CG2 4.90 Å between PHE 587 CB and PHE 575 CG 4.75 Å between PHE 587 CG and PHE 575 CG 4.34 Å between PHE 587 CD1 and PHE 575 CG 4.83 Å between PHE 587 CE1 and PHE 575 CG 4.93 Å between PHE 587 CZ and PHE 575 CD2 | 4.88 Å between ILE 587 CD1 and HIS 609 CG 3.99 Å between ILE 587 CG1 and VAL 591 CG2 4.91 Å between ILE 587 CD1 and VAL 591 CG2 4.80 Å between ILE 587 CB and PHE 575 CD2 4.58 Å between ILE 587 CG1 and PHE 575 CD2 4.93 Å between ILE 587 CD1 and PHE 575 CG |
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
F587 | I587 |
---|---|
none | none |
CYSMA's 3D visualizing module:
F587 (wild-type) | I587 (mutant) |
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JSmol Legends: The residue at the position 587 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å). Van der Waals contacts with the residue 587 are represented by dotted lines. Amino acids involved in H-bonds with the residue 587 are labelled in blue. Amino acids involved in steric clashes with the residue 587 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 F587I might correspond to:
Name | NM_000492.3:c.1759T>A |
Protein name | NP_000483.3:p.(Phe587Ile) |
Genomic name | chr7:g.117230486T>A |
Class | unclassified |
Total number of patients | 2 |
CFTR-RD | 1
|
Pending (NBS) | 1 |
(CFTR-France for more details)
Additional resources: |
The variation is not reported in Uniprot.
CYSMA Report: |
CFTR orthologs conservation | The wild-type residue F587 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs)The variant F587I has never been found among the CFTR orthologs |
NBD1 homologs conservation | The wild-type residue F587 belongs to the NBD1 domain and is conserved at 12.38% among the NBD1 homologs (493 / 3982 NBD1 homologs)
The variant F587I has been found among the NBD1 homologs with a non significant frequency: 4.85% (193 / 3982 NBD1 homologs) |
Structural effects | The wild-type residue PHE is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is reduced in the mutant residue ILE, which might slightly destabilize the region |
Allele frequency | The variant F587I in gnomAD (123,136 exomes): 4.01e-06 The variant F587V in gnomAD (123,136 exomes): 4.01e-06 |
Clinical significance | The variant F587I has not been reported in ClinVar |
CFTR-France | The variant F587I might correspond to: NM_000492.3:c.1759T>A, which is reported to be unclassified ( CFTR-France for more details) |
Additional resources | SIFT prediction: variant F587I is predicted to be damaging (score: 0.01) PPH2 prediction: variant F587I is predicted to be damaging (score: 1) |
CYSMA has completed its calculations; Execution time: 14 wallclock secs (11.23 usr 0.05 sys + 2.93 cusr 0.05 csys = 14.26 CPU)