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Analysis of p.Leu568Phe 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 F568 | Number of gaps | Conservation of L568 | Conservation - gap |
---|---|---|---|---|---|---|---|
50 | 80.72% | 91.61% | 1 show divergencies |
0 details |
0 details |
98.00% (49 / 50) | 98.00% (49 / 50) |
The wild-type residue L568 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs) The variant L568F 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 568). 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.Leu568 belongs to the domain NBD1.
423 |
| 649 |
|
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NBD1 of CF Transmembrane conductance Regulator domain alignment including p.Leu568 residue.
Number of sequences | AAPID*** (from aa 423 to aa 649) |
AAPIR! | Number of divergencies | Number of mutant | Number of gaps | Conservation of L568 | Conservation - gap |
---|---|---|---|---|---|---|---|
3982 | 26.61% | 45.41% | 2952 show divergencies |
94 | 2 | 25.82% (1028 / 3982) | 25.83% (1028 / 3980) |
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 568). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
The wild-type residue L568 belongs to the NBD1 domain and is conserved at 25.82% among the NBD1 homologs (1028 / 3982 NBD1 homologs)
The variant L568F has been found among the NBD1 homologs with a non significant frequency: 2.36% (94 / 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.Leu568 is predicted to belong to a β strand. Probability is 0.951.
Direct environment is as follow:
K | D | A | D | L568 | Y | L | L | D |
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Observed frequencies in β strands:
L: 1.1
F: 1.35
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.
L568 | F568 |
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none | none |
L568 | F568 |
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4.52 Å between LEU 568 CD2 and HIS 484 CD2 4.69 Å between LEU 568 CG and ILE 601 CD1 4.56 Å between LEU 568 CD1 and ILE 601 CG1 4.87 Å between LEU 568 CD2 and ILE 601 CD1 4.91 Å between LEU 568 CB and ILE 488 CB 4.52 Å between LEU 568 CD2 and ILE 488 CG1 4.72 Å between LEU 568 CG and LEU 570 CG 4.84 Å between LEU 568 CD1 and LEU 570 CD2 4.55 Å between LEU 568 CD2 and LEU 570 CG 4.15 Å between LEU 568 CD2 and ILE 471 CG2 4.64 Å between LEU 568 CG and VAL 392 CG2 3.65 Å between LEU 568 CD1 and VAL 392 CG2 4.38 Å between LEU 568 CD2 and VAL 392 CG2 | 4.20 Å between PHE 568 CD1 and ILE 488 CG1 4.88 Å between PHE 568 CE1 and ILE 488 CG1 4.84 Å between PHE 568 CB and LEU 570 CD2 4.72 Å between PHE 568 CG and VAL 392 CG2 4.63 Å between PHE 568 CD1 and VAL 392 CG2 4.19 Å between PHE 568 CD2 and VAL 392 CG2 3.96 Å between PHE 568 CE1 and VAL 392 CG2 4.90 Å between PHE 568 CE2 and VAL 392 CB 4.76 Å between PHE 568 CZ and VAL 392 CB |
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
L568 | F568 |
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none | 2.82 Å between PHE 568 CE1 and SER 485 O |
CYSMA's 3D visualizing module:
L568 (wild-type) | F568 (mutant) |
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JSmol Legends: The residue at the position 568 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å). Van der Waals contacts with the residue 568 are represented by dotted lines. Amino acids involved in H-bonds with the residue 568 are labelled in blue. Amino acids involved in steric clashes with the residue 568 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 L568F has not been described in CFTR-France
Additional resources: |
The variation is not reported in Uniprot.
CYSMA Report: |
CFTR orthologs conservation | The wild-type residue L568 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs)The variant L568F has never been found among the CFTR orthologs |
NBD1 homologs conservation | The wild-type residue L568 belongs to the NBD1 domain and is conserved at 25.82% among the NBD1 homologs (1028 / 3982 NBD1 homologs)
The variant L568F has been found among the NBD1 homologs with a non significant frequency: 2.36% (94 / 3982 NBD1 homologs) |
Structural effects | The wild-type residue LEU is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is reduced in the mutant residue PHE, which might slightly destabilize the region |
Allele frequency | The variant has not been reported in gnomAD |
Clinical significance | The variant L568F has not been reported in ClinVar |
CFTR-France | The variant L568F has not been described in CFTR-France |
Additional resources | SIFT prediction: variant L568F is predicted to be damaging (score: 0.02) PPH2 prediction: variant L568F is predicted to be damaging (score: 0.993) |
CYSMA has completed its calculations; Execution time: 13 wallclock secs (10.73 usr 0.04 sys + 2.82 cusr 0.06 csys = 13.65 CPU)