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Analysis of p.Val1114Leu 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 L1114 | Number of gaps | Conservation of V1114 | Conservation - gap |
---|---|---|---|---|---|---|---|
50 | 80.72% | 82.81% | 5 show divergencies |
0 details |
0 details |
90.00% (45 / 50) | 90.00% (45 / 50) |
The wild-type residue V1114 is highly conserved among the CFTR orthologs: 90% (45 / 50 CFTR orthologs) The variant V1114L 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 1114). 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.Val1114 belongs to the domain MSD2.
844 |
| 1203 |
|
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MSD2 of CF Transmembrane conductance Regulator domain alignment including p.Val1114 residue.
Number of sequences | AAPID*** (from aa 844 to aa 1203) |
AAPIR! | Number of divergencies | Number of mutant | Number of gaps | Conservation of V1114 | Conservation - gap |
---|---|---|---|---|---|---|---|
127 | 34.22% | 27.35% | 77 show divergencies |
5 | 0 | 39.37% (50 / 127) | 39.37% (50 / 127) |
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 1114). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
The wild-type residue V1114 belongs to the MSD2 domain and is conserved at 39.37% among the MSD2 homologs (50 / 127 MSD2 homologs)
The variant V1114L has been found among the MSD2 homologs with a non significant frequency: 3.94% (5 / 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.Val1114 is predicted to belong to an α helice. Probability is 0.975.
Direct environment is as follow:
F | F | I | A | V1114 | T | F | I | S |
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Observed frequencies in α helices:
V: 0.88
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.
V1114 | L1114 |
---|---|
none | none |
V1114 | L1114 |
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3.78 Å between VAL 1114 CG1 and ILE 1132 CG2 4.90 Å between VAL 1114 CB and PHE 1110 CE2 4.37 Å between VAL 1114 CG2 and PHE 1110 CG 4.77 Å between VAL 1114 CB and ILE 1015 CG1 4.66 Å between VAL 1114 CG1 and ILE 1015 CG1 4.75 Å between VAL 1114 CG2 and ILE 1015 CB 4.88 Å between VAL 1114 CG1 and VAL 1008 CG1 | 3.69 Å between LEU 1114 CD1 and ALA 1136 CB 4.78 Å between LEU 1114 CG and PHE 1110 CG 4.05 Å between LEU 1114 CD1 and PHE 1110 CD2 5.00 Å between LEU 1114 CD2 and PHE 1110 CG 4.97 Å between LEU 1114 CG and ILE 1015 CG2 4.25 Å between LEU 1114 CD2 and ILE 1015 CB 4.48 Å between LEU 1114 CD1 and PHE 1111 CD1 4.42 Å between LEU 1114 CD2 and VAL 1008 CG1 |
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
V1114 | L1114 |
---|---|
none | 2.96 Å between LEU 1114 CB and THR 1115 N |
CYSMA's 3D visualizing module:
V1114 (wild-type) | L1114 (mutant) |
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JSmol Legends: The residue at the position 1114 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å). Van der Waals contacts with the residue 1114 are represented by dotted lines. Amino acids involved in H-bonds with the residue 1114 are labelled in blue. Amino acids involved in steric clashes with the residue 1114 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 V1114L might correspond to:
Name | NM_000492.3:c.3340G>C |
Protein name | NP_000483.3:p.(Val1114Leu) |
Genomic name | chr7:g.117251835G>C |
Class | unclassified |
No patient found |
(CFTR-France for more details)
Additional resources: |
The variation is not reported in Uniprot.
CYSMA Report: |
CFTR orthologs conservation | The wild-type residue V1114 is highly conserved among the CFTR orthologs: 90% (45 / 50 CFTR orthologs)The variant V1114L has never been found among the CFTR orthologs |
MSD2 homologs conservation | The wild-type residue V1114 belongs to the MSD2 domain and is conserved at 39.37% among the MSD2 homologs (50 / 127 MSD2 homologs)
The variant V1114L has been found among the MSD2 homologs with a non significant frequency: 3.94% (5 / 127 MSD2 homologs) |
Structural effects | The wild-type residue VAL is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is maintained in the mutant residue LEU |
Allele frequency | The variant V1114L in gnomAD (123,136 exomes): 3.99e-06 |
Clinical significance | The variant V1114L has not been reported in ClinVar |
CFTR-France | The variant V1114L might correspond to: NM_000492.3:c.3340G>C, which is reported to be unclassified ( CFTR-France for more details) |
Additional resources | SIFT prediction: variant V1114L is predicted to be damaging (score: 0.04) PPH2 prediction: variant V1114L is predicted to be benign (score: 0.058) |
CYSMA has completed its calculations; Execution time: 11 wallclock secs ( 7.68 usr 0.03 sys + 3.01 cusr 0.05 csys = 10.77 CPU)