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Analysis of p.Leu467Phe 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 F467 | Number of gaps | Conservation of L467 | Conservation - gap |
---|---|---|---|---|---|---|---|
50 | 80.72% | 86.34% | 0 show divergencies |
0 details |
0 details |
100.00% (50 / 50) | 100.00% (50 / 50) |
The wild-type residue L467 is conserved at 100% among the CFTR orthologs
*AAPI: Alignment Average Percentage Identity
**AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 467). 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.Leu467 (NBD1) seems to play a key role in the CFTR function:
p.Leu467 is involved in the CFTR folding.
The residue p.Leu467 belongs to the domain NBD1.
423 |
| 649 |
|
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NBD1 of CF Transmembrane conductance Regulator domain alignment including p.Leu467 residue.
Number of sequences | AAPID*** (from aa 423 to aa 649) |
AAPIR! | Number of divergencies | Number of mutant | Number of gaps | Conservation of L467 | Conservation - gap |
---|---|---|---|---|---|---|---|
3982 | 26.61% | 67.87% | 1140 show divergencies |
257 | 6 | 71.22% (2836 / 3982) | 71.33% (2836 / 3976) |
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 467). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
The wild-type residue L467 belongs to the NBD1 domain and is conserved at 71.22% among the NBD1 homologs (2836 / 3982 NBD1 homologs)
The variant L467F has been found among the NBD1 homologs with a notable frequency: 6.45% (257 / 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.Leu467 is predicted to belong to an α helice. Probability is 0.941.
Direct environment is as follow:
G | K | T | S | L467 | L | M | V | I |
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Observed frequencies in α helices:
L: 1.16
F: 0.97
Mutant residue is less 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.
L467 | F467 |
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none | none |
L467 | F467 |
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4.40 Å between LEU 467 CD2 and VAL 456 CB 4.23 Å between LEU 467 CD1 and ILE 444 CG2 4.27 Å between LEU 467 CB and LEU 468 CD1 4.79 Å between LEU 467 CG and LEU 468 CD1 4.81 Å between LEU 467 CD2 and LEU 468 CD1 4.99 Å between LEU 467 CD1 and VAL 470 CG2 4.68 Å between LEU 467 CD1 and LEU 619 CD1 4.61 Å between LEU 467 CD2 and LEU 619 CD1 4.76 Å between LEU 467 CD1 and PHE 446 CE1 4.70 Å between LEU 467 CB and LEU 441 CD1 4.49 Å between LEU 467 CD1 and LEU 441 CD1 | 4.71 Å between PHE 467 CG and VAL 456 CG1 4.98 Å between PHE 467 CD1 and VAL 456 CG1 4.69 Å between PHE 467 CD2 and VAL 456 CG1 4.96 Å between PHE 467 CE2 and VAL 456 CG1 4.91 Å between PHE 467 CZ and VAL 456 CG2 4.88 Å between PHE 467 CE2 and ILE 601 CG2 4.98 Å between PHE 467 CD1 and ILE 444 CG2 3.97 Å between PHE 467 CE1 and ILE 444 CG2 4.29 Å between PHE 467 CZ and ILE 444 CG2 4.69 Å between PHE 467 CE2 and LEU 454 CD2 4.21 Å between PHE 467 CB and LEU 468 CD2 4.67 Å between PHE 467 CD2 and LEU 468 CD1 4.70 Å between PHE 467 CE1 and LEU 617 CD2 4.34 Å between PHE 467 CZ and LEU 617 CD2 4.74 Å between PHE 467 CG and LEU 619 CD1 3.75 Å between PHE 467 CD1 and LEU 619 CD1 4.95 Å between PHE 467 CE1 and LEU 619 CG 4.84 Å between PHE 467 CZ and LEU 619 CD1 4.34 Å between PHE 467 CE1 and PHE 446 CE1 4.79 Å between PHE 467 CE2 and PHE 446 CD1 4.11 Å between PHE 467 CZ and PHE 446 CD1 4.51 Å between PHE 467 CD1 and LEU 441 CD1 4.89 Å between PHE 467 CD2 and ILE 471 CD1 4.99 Å between PHE 467 CE2 and ILE 471 CD1 |
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
L467 | F467 |
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none | none |
CYSMA's 3D visualizing module:
L467 (wild-type) | F467 (mutant) |
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JSmol Legends: The residue at the position 467 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å). Van der Waals contacts with the residue 467 are represented by dotted lines. Amino acids involved in H-bonds with the residue 467 are labelled in blue. Amino acids involved in steric clashes with the residue 467 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 L467F might correspond to:
Name | NM_000492.3:c.1399C>T |
Protein name | NP_000483.3:p.(Leu467Phe) |
Genomic name | chr7:g.117199524C>T |
Class | unclassified |
Total number of patients | 13 |
CF | 9 |
CFTR-RD | 4
|
(CFTR-France for more details)
Additional resources: |
The variation is not reported in Uniprot.
CYSMA Report: |
CFTR orthologs conservation | The wild-type residue L467 is conserved at 100% among the CFTR orthologs |
NBD1 homologs conservation | The wild-type residue L467 belongs to the NBD1 domain and is conserved at 71.22% among the NBD1 homologs (2836 / 3982 NBD1 homologs)
The variant L467F has been found among the NBD1 homologs with a notable frequency: 6.45% (257 / 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 maintained in the mutant residue PHE |
Allele frequency | The variant L467F in gnomAD (123,136 exomes): 3.98e-05 ; variant L467F in gnomAD (15,496 genomes): 3.18e-05 The variant L467P in gnomAD (123,136 exomes): 7.96e-06 ; variant L467P in gnomAD (15,496 genomes): 3.19e-05 |
Clinical significance | The variant L467F has been been described as Conflicting interpretations of pathogenicity - criteria provided, conflicting interpretations - (ClinVar for more details) |
CFTR-France | The variant L467F might correspond to: NM_000492.3:c.1399C>T, which is reported to be unclassified ( CFTR-France for more details) |
Additional resources | SIFT prediction: variant L467F is predicted to be damaging (score: 0) PPH2 prediction: variant L467F is predicted to be damaging (score: 1) |
CYSMA has completed its calculations; Execution time: 14 wallclock secs (10.04 usr 0.03 sys + 3.01 cusr 0.05 csys = 13.13 CPU)