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Analysis of p.Ile980Met 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 M980 | Number of gaps | Conservation of I980 | Conservation - gap |
|---|---|---|---|---|---|---|---|
| 50 | 80.72% | 83.28% | 12 show divergencies |
6 details |
0 details |
76.00% (38 / 50) | 76.00% (38 / 50) |
The wild-type residue I980 is highly conserved among the CFTR orthologs: 76% (38 / 50 CFTR orthologs)
The variant I980M has been found among the CFTR orthologs with a high frequency: 12% (6 / 50 CFTR orthologs)
*AAPI: Alignment Average Percentage Identity
**AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 980). 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.Ile980 (MSD2) seems to play a key role in the CFTR function:
p.Ile980 is involved in the CFTR folding.
The residue p.Ile980 belongs to the domain MSD2.
| 844 |
| 1203 |
MSD2: is the membrane-spanning domain 2, composed of six transmembrane helices (TM7-TM12).
Four of the six TMs protrude into the cytosol to form the intracellular loops. ICL3 (between TM8 and TM9) and ICL4 (between TM10 and TM11). ICL3 contacts the NBD2 at the level of the ATP-binding site, while ICL4 binds in a groove located at the surface of NBD1.
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MSD2 of CF Transmembrane conductance Regulator domain alignment including p.Ile980 residue.
| Number of sequences | AAPID*** (from aa 844 to aa 1203) |
AAPIR! | Number of divergencies | Number of mutant | Number of gaps | Conservation of I980 | Conservation - gap |
|---|---|---|---|---|---|---|---|
| 127 | 34.22% | 53.75% | 69 show divergencies |
22 | 0 | 45.67% (58 / 127) | 45.67% (58 / 127) |
***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
!AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 980). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.
The wild-type residue I980 belongs to the MSD2 domain and is conserved at 45.67% among the MSD2 homologs (58 / 127 MSD2 homologs)
The variant I980M has been found among the MSD2 homologs with a high frequency: 17.32% (22 / 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:
| Secondary structure analysis: |
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Residue p.Ile980 is predicted to belong to an α helice. Probability is 0.768.
Direct environment is as follow:
| F | S | K | D | I980 | A | I | L | D |
 |  | | |  |  | | | |
Observed frequencies in α helices:
I: 0.99
M: 1.14
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.
| I980 | M980 |
|---|---|
| none | none |
| I980 | M980 |
|---|---|
| 5.00 Å between ILE 980 CB and LEU 983 CB 4.76 Å between ILE 980 CG1 and LEU 983 CB 4.75 Å between ILE 980 CG1 and HIS 949 CB 3.99 Å between ILE 980 CD1 and HIS 949 CG | 4.78 Å between MET 980 CG and MET 952 CE 4.38 Å between MET 980 CE and HIS 949 CG |
For hydrophobic effects, the important point is the number of residues involved more than the number of interactions.
| I980 | M980 |
|---|---|
| none | none |
CYSMA's 3D visualizing module:
| I980 (wild-type) | M980 (mutant) |
|---|---|
JSmol Legends:
The residue at the position 980 is located in the center, labelled in yellow and surrounded by its neighboring residues (distance < 5 Å).
Van der Waals contacts with the residue 980 are represented by dotted lines.
Amino acids involved in H-bonds with the residue 980 are labelled in blue.
Amino acids involved in steric clashes with the residue 980 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 I980M might correspond to:
| Name | NM_000492.3:c.2940A>G |
| Protein name | NP_000483.3:p.(Ile980Met) |
| Genomic name | chr7:g.117246759A>G |
| Class | unclassified |
| Total number of patients | 1 |
| CFTR-RD | 1
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(CFTR-France for more details)
| Additional resources: |
The variation is not reported in Uniprot.
| CYSMA Report: |
| CFTR orthologs conservation | The wild-type residue I980 is highly conserved among the CFTR orthologs: 76% (38 / 50 CFTR orthologs) The variant I980M has been found among the CFTR orthologs with a high frequency: 12% (6 / 50 CFTR orthologs) |
| MSD2 homologs conservation | The wild-type residue I980 belongs to the MSD2 domain and is conserved at 45.67% among the MSD2 homologs (58 / 127 MSD2 homologs)
The variant I980M has been found among the MSD2 homologs with a high frequency: 17.32% (22 / 127 MSD2 homologs) |
| Structural effects | |
| Allele frequency | The variant has not been reported in gnomAD |
| Clinical significance | The variant I980M has not been reported in ClinVar |
| CFTR-France | The variant I980M might correspond to: NM_000492.3:c.2940A>G, which is reported to be unclassified ( CFTR-France for more details) |
| Additional resources |
SIFT prediction: variant I980M is predicted to be tolerated (score: 0.41) PPH2 prediction: variant I980M is predicted to be benign (score: 0) |
CYSMA has completed its calculations; Execution time: 14 wallclock secs ( 9.49 usr 0.04 sys + 3.59 cusr 0.06 csys = 13.18 CPU)
