![]() |
![]() ![]() ![]() |
Analysis of p.Ile1234Val 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: |
![]() |
Number of sequences | AAPI* | AAPIR** | Number of divergencies | Number of mutant V1234 | Number of gaps | Conservation of I1234 | Conservation - gap |
---|---|---|---|---|---|---|---|
50 | 80.72% | 83.87% | 8 show divergencies |
5 details |
0 details |
84.00% (42 / 50) | 84.00% (42 / 50) |
The wild-type residue I1234 is highly conserved among the CFTR orthologs: 84% (42 / 50 CFTR orthologs) The variant I1234V has been found among the CFTR orthologs with a high frequency: 10% (5 / 50 CFTR orthologs)
*AAPI: Alignment Average Percentage Identity
**AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 1234). 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: |
![]() |
The domain NBD2 of CF Transmembrane conductance Regulator has been shown to interact with:
The residue p.Ile1234 belongs to the domain NBD2.
1210 |
| 1443 |
|
|||
![]() |
NBD2 of CF Transmembrane conductance Regulator domain alignment including p.Ile1234 residue.
Number of sequences | AAPID*** (from aa 1210 to aa 1443) |
AAPIR! | Number of divergencies | Number of mutant | Number of gaps | Conservation of I1234 | Conservation - gap |
---|---|---|---|---|---|---|---|
715 | 24.58% | 28.82% | 495 show divergencies |
225 | 0 | 30.77% (220 / 715) | 30.77% (220 / 715) |
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 1234). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
The wild-type residue I1234 belongs to the NBD2 domain and is conserved at 30.77% among the NBD2 homologs (220 / 715 NBD2 homologs)
The variant I1234V has been found among the NBD2 homologs with a very high frequency: 31.47% (225 / 715 NBD2 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 NBD2 domain conservation:
Refer to the Help page for more details.
Secondary structure analysis: |
![]() |
Residue p.Ile1234 is predicted to belong to a β strand. Probability is 0.932.
Direct environment is as follow:
I | S | F | S | I1234 | S | P | G | Q |
![]() | ![]() | ![]() | ![]() | ![]() | ![]() | ![]() | ![]() | ![]() |
Observed frequencies in β strands:
I: 1.6
V: 1.8
Mutant residue is more observed in this type of structure.
3D analysis: |
![]() |
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.
I1234 | V1234 |
---|---|
none | none |
I1234 | V1234 |
---|---|
4.30 Å between ILE 1234 CG1 and PHE 1232 CD2 4.70 Å between ILE 1234 CD1 and PHE 1232 CD2 4.80 Å between ILE 1234 CG2 and VAL 1240 CB 4.39 Å between ILE 1234 CG1 and LEU 1414 CD1 4.20 Å between ILE 1234 CD1 and LEU 1414 CD1 4.86 Å between ILE 1234 CD1 and ILE 1398 CG1 4.38 Å between ILE 1234 CB and MET 1210 CB 4.74 Å between ILE 1234 CG1 and MET 1210 CB 4.67 Å between ILE 1234 CD1 and MET 1210 CB | 4.45 Å between VAL 1234 CG2 and PHE 1232 CD2 4.94 Å between VAL 1234 CB and VAL 1240 CG2 4.95 Å between VAL 1234 CG1 and VAL 1240 CB 4.98 Å between VAL 1234 CG2 and VAL 1240 CG2 4.87 Å between VAL 1234 CG2 and LEU 1414 CG 4.69 Å between VAL 1234 CB and MET 1210 CB 3.91 Å between VAL 1234 CG2 and MET 1210 CE |
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
I1234 | V1234 |
---|---|
none | none |
CYSMA's 3D visualizing module:
I1234 (wild-type) | V1234 (mutant) |
---|---|
JSmol Legends: The residue at the position 1234 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å). Van der Waals contacts with the residue 1234 are represented by dotted lines. Amino acids involved in H-bonds with the residue 1234 are labelled in blue. Amino acids involved in steric clashes with the residue 1234 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 I1234V might correspond to:
Name | NM_000492.3:c.3700A>G |
Protein name | NP_000483.3:p.(Ile1234Val) |
Genomic name | chr7:g.117267807A>G |
Class | disease-causing |
Total number of patients | 7 |
CF | 6 |
CFTR-RD | 1
|
(CFTR-France for more details)
Additional resources: |
Reference | PMID | Splicing | mRNA level | Maturation | Localization | Channel fonction (Cl-) | Bicarbonate |
Sosnay et al, 2013 | 23974870 | ✓ | ✓ | ||||
Ramalho et al, 2016 | 25735457 | ✓ | ✓ | ✓ | ✓ | ✓ |
« ✓ » indicates the type of analysis performed and not the results
The variation is not reported in Uniprot.
CYSMA Report: |
CFTR orthologs conservation | The wild-type residue I1234 is highly conserved among the CFTR orthologs: 84% (42 / 50 CFTR orthologs)The variant I1234V has been found among the CFTR orthologs with a high frequency: 10% (5 / 50 CFTR orthologs) |
NBD2 homologs conservation | The wild-type residue I1234 belongs to the NBD2 domain and is conserved at 30.77% among the NBD2 homologs (220 / 715 NBD2 homologs)
The variant I1234V has been found among the NBD2 homologs with a very high frequency: 31.47% (225 / 715 NBD2 homologs) |
Structural effects | The wild-type residue ILE is buried and is likely to belong to a hydrophobic pocket or core. This hydrophobic core is maintained in the mutant residue VAL |
Allele frequency | The variant I1234V in gnomAD (123,136 exomes): 4.02e-06 |
Clinical significance | The variant I1234V has been been described as Pathogenic - reviewed by expert panel - (ClinVar for more details) |
CFTR-France | The variant I1234V might correspond to: NM_000492.3:c.3700A>G, which is reported to be disease-causing ( CFTR-France for more details) |
Additional resources | SIFT prediction: variant I1234V is predicted to be tolerated (score: 0.81) PPH2 prediction: variant I1234V is predicted to be benign (score: 0.001) |
CYSMA has completed its calculations; Execution time: 12 wallclock secs ( 8.13 usr 0.03 sys + 3.34 cusr 0.06 csys = 11.56 CPU)