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Analysis of p.Phe1074Leu 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 L1074 | Number of gaps | Conservation of F1074 | Conservation - gap |
---|---|---|---|---|---|---|---|
50 | 80.72% | 92.28% | 1 show divergencies |
0 details |
0 details |
98.00% (49 / 50) | 98.00% (49 / 50) |
The wild-type residue F1074 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs) The variant F1074L 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 1074). 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 MSD2 of CF Transmembrane conductance Regulator has been shown to interact with:
The residue p.Phe1074 belongs to the domain MSD2.
844 |
| 1203 |
|
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MSD2 of CF Transmembrane conductance Regulator domain alignment including p.Phe1074 residue.
Number of sequences | AAPID*** (from aa 844 to aa 1203) |
AAPIR! | Number of divergencies | Number of mutant | Number of gaps | Conservation of F1074 | Conservation - gap |
---|---|---|---|---|---|---|---|
127 | 34.22% | 38.55% | 14 show divergencies |
1 | 0 | 88.98% (113 / 127) | 88.98% (113 / 127) |
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 1074). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
The wild-type residue F1074 belongs to the MSD2 domain and is conserved at 88.98% among the MSD2 homologs (113 / 127 MSD2 homologs)
The variant F1074L has been found among the MSD2 homologs with a non significant frequency: 0.79% (1 / 127 MSD2 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 MSD2 domain conservation:
Refer to the Help page for more details.
Secondary structure analysis: |
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Residue p.Phe1074 is predicted to belong to an α helice. Probability is 0.977.
Direct environment is as follow:
R | Q | P | Y | F1074 | E | T | L | F |
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Observed frequencies in α helices:
F: 0.97
L: 1.16
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 % | 17/1474 - 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.
F1074 | L1074 |
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none | none |
F1074 | L1074 |
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4.57 Å between PHE 1074 CB and LEU 1065 CD1 4.63 Å between PHE 1074 CG and LEU 1065 CG 4.50 Å between PHE 1074 CD1 and LEU 1065 CG 4.87 Å between PHE 1074 CD2 and LEU 1065 CG 4.62 Å between PHE 1074 CE1 and LEU 1065 CG 4.98 Å between PHE 1074 CE2 and LEU 1065 CG 4.87 Å between PHE 1074 CZ and LEU 1065 CG 4.76 Å between PHE 1074 CG and TYR 1073 CD2 4.62 Å between PHE 1074 CD1 and TYR 1073 CB 4.07 Å between PHE 1074 CE1 and TYR 1073 CD2 4.32 Å between PHE 1074 CE1 and PHE 508 CE1 4.98 Å between PHE 1074 CZ and PHE 508 CZ 4.87 Å between PHE 1074 CB and HIS 1054 CE1 4.98 Å between PHE 1074 CG and HIS 1054 CE1 4.45 Å between PHE 1074 CD2 and HIS 1054 CE1 4.86 Å between PHE 1074 CB and TYR 161 CE2 | 4.71 Å between LEU 1074 CB and LEU 1065 CD1 4.01 Å between LEU 1074 CG and LEU 1065 CD1 5.00 Å between LEU 1074 CD1 and LEU 1065 CD1 4.32 Å between LEU 1074 CD2 and LEU 1065 CD1 4.42 Å between LEU 1074 CD2 and TYR 1073 CB 4.55 Å between LEU 1074 CD1 and LEU 1077 CB 4.66 Å between LEU 1074 CD1 and HIS 1054 CE1 |
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
F1074 | L1074 |
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none | none |
CYSMA's 3D visualizing module:
F1074 (wild-type) | L1074 (mutant) |
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JSmol Legends: The residue at the position 1074 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å). Van der Waals contacts with the residue 1074 are represented by dotted lines. Amino acids involved in H-bonds with the residue 1074 are labelled in blue. Amino acids involved in steric clashes with the residue 1074 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 F1074L 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 F1074 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs)The variant F1074L has never been found among the CFTR orthologs |
MSD2 homologs conservation | The wild-type residue F1074 belongs to the MSD2 domain and is conserved at 88.98% among the MSD2 homologs (113 / 127 MSD2 homologs)
The variant F1074L has been found among the MSD2 homologs with a non significant frequency: 0.79% (1 / 127 MSD2 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 LEU, which might slightly destabilize the region |
Allele frequency | The variant F1074L in gnomAD (123,136 exomes): 3.98e-06 The variant F1074L in gnomAD (123,136 exomes): 3.98e-06 |
Clinical significance | The variant F1074L has not been reported in ClinVar |
CFTR-France | The variant F1074L has not been described in CFTR-France |
Additional resources | SIFT prediction: variant F1074L is predicted to be tolerated (score: 0.08) PPH2 prediction: variant F1074L is predicted to be damaging (score: 0.999) |
CYSMA has completed its calculations; Execution time: 11 wallclock secs ( 7.65 usr 0.04 sys + 2.99 cusr 0.06 csys = 10.74 CPU)