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Analysis of p.Ala46Asp 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:

    The variant has not been reported in gnomAD


  • Ortholog conservation: Help


    Number of sequences AAPI* AAPIR** Number of divergencies Number of mutant D46 Number of gaps Conservation of A46 Conservation - gap
    50 80.72% 83.57% 1
    show divergencies
    0
    details
    0
    details
    98.00% (49 / 50) 98.00% (49 / 50)


    The wild-type residue A46 is highly conserved among the CFTR orthologs: 98% (49 / 50 CFTR orthologs)
    The variant A46D 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 46). 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



    Display methods


  • Domain conservation: Help

    The domain N-ter of CF Transmembrane conductance Regulator has been shown to interact with:



    The residue p.Ala46 (N-ter) seems to play a key role in the CFTR function:

    p.Ala46 belongs to the lasso motif and is involved in the CFTR folding.


    The residue p.Ala46 belongs to the domain N-ter.

    1
    68


    N-ter: N-terminal region is a cytosolic region, also called the "lasso motif" because of its shape.
    The first 40 residues are partially inserted into the membrane, while the end form the "lasso" helix (Zhang et al., 2016).








    N-ter of CF Transmembrane conductance Regulator domain alignment including p.Ala46 residue.



    Number of sequences AAPID***
    (from aa 1 to aa 68)
    AAPIR! Number of divergencies Number of mutant Number of gaps Conservation of A46 Conservation - gap
    123 35.55% 31.11% 57
    show divergencies
    0 0 53.66% (66 / 123) 53.66% (66 / 123)



    ***AAPID: Alignment Average Percentage Identity of the Domain (positions are indicated).
    !AAPIR: Alignment Average Percentage Identity of the Region (20 residues surrounding position 46). AAPIR appears in green if it is more than 10% compared to AAPID, in red if less than 10%.

    The wild-type residue A46 belongs to the N-ter domain and is conserved at 53.66% among the N-ter homologs (66 / 123 N-ter homologs)
    The variant A46D has never been found among the N-ter 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 N-ter domain conservation:





    Display methods


  • Refer to the Help page for more details.


  • Secondary structure analysis: Help


    Residue p.Ala46 is predicted to belong to an α helice. Probability is 0.590.

    Direct environment is as follow:

    SVDSA46DNLS
    CCCCHHHHH


    Observed frequencies in α helices:
    A: 1.23
    D: 0.98

    Mutant residue is less observed in this type of structure.

    Display methods











  • 3D analysis: Help


    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.


  • Clinical significance:

    The variant A46D has been been described as Pathogenic - reviewed by expert panel - (ClinVar for more details)


  • Patients data: CFTR-France

  • Variant A46D might correspond to:


    Variant details from CFTR-France:
    Name NM_000492.3:c.137C>A
    Protein name NP_000483.3:p.(Ala46Asp)
    Genomic name chr7:g.117144390C>A
    Class disease-causing


    Patients carrying this variant in CFTR-France:
    Total number of patients 4
    CF 3
    CFTR-RD1
    • Bronchiectasis  1

    (CFTR-France for more details)




  • Additional resources:



  • References


    CYSMA has completed its calculations; Execution time: 10 wallclock secs ( 7.77 usr 0.03 sys + 2.98 cusr 0.06 csys = 10.84 CPU)