Looking Ahead to Change: Little by Little
I don't make New Year's Resolutions. I don't think I ever really did, but the last decade or two would have been enough to stifle that impulse. I've just been too aware that I don't have that much control over what happens in my life.
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Rare allele data

Discussion in 'Genetic Testing and SNPs' started by Valentijn, Jun 28, 2013.

  1. MegHurley36

    MegHurley36

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    I DO have a nutreval too if that helps correlate. I will NOT post that here, but I can send via msg if you like
     
  2. Valentijn

    Valentijn Senior Member

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    Nothing too bad :D Basically the program pulled out 92 very rare results.

    30 of those aren't on genes, so aren't directly doing anything. Another 45 SNPs are on introns, so they are non-coding SNPs and usually have little or no direct impact on gene functioning. It's possible that they're reflecting a rare SNP which is somewhere more interesting, but there's no way to know, so there's no point in speculating about that.

    So that leaves 17 which are missense mutations.

    Only one of those is thought to be pathogenic, i5007196 (rs121908601), which is heterozygous in 1.7% of the general population. It might cause "Sporadic Tetralogy of Fallot" even when it's heterozygous. It's described a bit at http://omim.org/entry/603693#0002 and there's links to the research there.

    However, single case studies can misidentify SNPs as being responsible for a disease when they aren't, so it's far from conclusive about anything. Basically if it is causing issues, it would be relatively mild and intermittent heart problems, especially in regards to oxygenating the blood. So it could potentially cause "fatigue" and other symptoms very similar to Orthostatic Intolerance.

    The other missense mutations don't have any data indicating if they're pathogenic or not. But there is a nice utility which assesses mutations to determine the likelihood of them being pathogenic. This is typically based on the rarity of the mutation, the location of it on the coded protein, the amino acid which is replacing the normal one, etc.

    10 of those mutations have relatively low probability of causing much impact on the gene. They're listed here with rs number, percentage likelihood that they have serious impact, gene name, and mutation identification:
    rs11243406 - 13% (POMT1 D433E)
    rs35956182 - 14% (SLC22A1 M440I)
    rs12116440 - 25% (AK2 A209T)
    rs11575840 - 29% (NCR3 A103T)
    rs3731062 - 45% (XPC L48F)
    rs1046166 - 51% (LARGE R665H)
    rs3918018 - 54% (CSF3R D320N)
    rs2234080 - 64% (ETV7 A250V)
    rs36105360 - 68% (LMNB1 A501V)
    rs34130495 - 69% (SLC22A1 G401S)
    The only potentially worrisome aspect here is that you have two distinct missense mutations on SLC22A1. While the odds of them each causing problems is relatively low, there's a chance that they're working together to cause a problem with that gene.

    rs17201603 doesn't have sufficient data to calculate the probability, but an amino acid is being replaced by another amino acid which is functionally very different. This usually creates a higher risk of problems.

    And there are 5 SNPs which have a relatively good shot at impacting gene function. However, these are all heterozygous, which usually (but not always) prevents them from causing much of a problem. Of course, it's also possible that any of these changes represent increased functionality, rather than decreased:
    rs17327630 - 85% (DEFB119 C49F)
    rs61754582 - 85% (GDF9 R454C)
    rs35629723 - 87% (WDR36 D33E)
    i5009017 (rs116040871) - 88% (SIRT1 E536K)
    rs41279857 - 89% (CYP3A5 S100Y)

    DEFB119 is a gene involved in protecting against microbial infections.
    GDF9 is a gene involved in ovarian folliculogenesis.
    WDR36 is a gene involved in T-cell activation.
    SIRT1 is a regulatory gene which deacetylates other gene products.
    CYPE3A5 is one of the many genes involved in drug metabolism and lipid synthesis.

    Anyhow, it might give you some things to look into, if the potential effects of these genes match up with your symptoms or health problems to some extend.
     
    Last edited: Feb 19, 2015
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  3. MegHurley36

    MegHurley36

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    Thank you! I may have found a culprit with regard to the toxicity I experienced when taking the fluoroquinolone (which others may want to look at) The CYP3A5 AND rs34130495 SLC22A1. Quinines and CoQ10 (now what can I use to replace coq10!) Cross my mitochondrial cell membranes in both directions! couple the slc with CYP, that would give me a fast absorption as well as trapping within cells....As well, this means, per the below info on the rs, the meds and foods/supplements are something I will get a mssive response to, positive or negative. I wonder if this added to the SLC's which deal with G6PC are expressing, and hence, causing the acidosis. This too would explain the awful reactions I now have to ANY synthetic medicine and/or antibiotic, SLC22A1 is active as it were.

    Here is a link I pulled the info from:
    http://www.uniprot.org/uniprot/O15245
    • Subcell. location
    • Pathol./Biotech
    • PTM / Processing
    • Expression
    • Interaction
    • Structure
    • Family & Domains
    • Sequences (4)
    • Cross-references
    • Publications
    • Entry information
    • Miscellaneous
    • Similar proteins
    BLAST
    Functioni
    Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin-dependent kinase II and LCK tyrosine kinase.

    Now, how to turn it back OFF is the question of the year. I have to have lipids and coq10! right? You are so awesome to help me with this it has been years of me getting bits better, but stuck. This i think is key. Now, I need someone somewhere in this world to help me correlate to my nutreval def. Then I can put things into practice to heal. ps. I am on a diet similar to wahl protocol, i did not know hers existed until recently..... However, I did remove foods closely tied to G6PD as my symptoms now, notwithstanding CFS, follow the same lines as it too works along the 6-glosphate line.

    Every few months, I get massive fatigue, bruising, anema, brain fog, brittle hair, dizzy, weight loss, and rashes. Some I have to some extent always now.
     
    Last edited: Feb 19, 2015
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  4. SDSue

    SDSue Southeast

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    @Valentijn - Apologies if this has already been asked but when I try to run my data I get the following message:

    Error: Data to start rs….

    Any ideas? Thanks.
     
  5. Valentijn

    Valentijn Senior Member

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    I'm not sure what would cause that. Can you send me a screen shot via private message, or post it here?
     
  6. SDSue

    SDSue Southeast

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    @Valentijn I got it figured out. Thanks so much.

    Looks like my homozygous whammy is on rs10482653, which according to your chart here, is a problem even if just hetero. Yikes.
     
  7. Valentijn

    Valentijn Senior Member

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    Actually there's no indication that it causes problems ... that chart was just looking at patient results versus control results. It's not on a coding section of the gene, so probably isn't doing much.
     
  8. SDSue

    SDSue Southeast

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    Gotcha. That's good to know. What would we do without you!
     
  9. Valentijn

    Valentijn Senior Member

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    :love:
     
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  10. MegHurley36

    MegHurley36

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    TY @Valentijn

    Soooo, I need to run that thingamajig lol, you have to show me the snps associated with the RS #'s mis sense. Where or how do I find that thing again that pulls the 1%'ers and shows me which they are: I ran the one, but I cannot seem to run the gene.rename after extraction. Isnt that what I use to find the alleles w gene names> Lost as usual.

    Here is what I ran:
     

    Attached Files:

  11. Valentijn

    Valentijn Senior Member

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    Is it the 10% file which you want to run now? It has to be downloaded separately from http://sourceforge.net/projects/analyzemygenes/files/Databases/ , then you can put it in the same directory with the one_percent file and it should be easy to find.
     
  12. heyitisjustin

    heyitisjustin Senior Member

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    What can one do with the results of the program? For example, I have these 1% homozygous mutations
    rs10512749,5,T,0.010,TT,,Y
    rs10505888,12,A,0.010,AA,,Y
    rs1048945,14,C,0.010,CC,,Y

    I tried to look them up on SNPedia and didn't see anything on them. Is there another resource we should be checking our SNPs against?
     
  13. Valentijn

    Valentijn Senior Member

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    This is on a suspected gene, though nothing is known about it yet. Allele frequency is 2.06%, so calculated homozygous frequency should be 0.06%. But for the thousands of people actually tested in the databases, none are homozygous.

    This isn't on a gene and is very far away from any genes. So it doesn't do anything, and probably isn't reflective of nearby mutations which can do something.

    This is a missense mutation on the APEX1 gene. That gene is involved with DNA repair of damage from oxidative stress, and the gene is associated with Attenuated Familial Adenomatous Polyposis and Pituitary-Dependent Cushing's Disease.

    The specific mutation itself isn't known to be either benign or pathogenic. On a BLOSUM62 chart, comparing how drastic the change of amino acids is likely to be, it's right in the middle. Minor allele prevalence is 2.06%, so should also be prevalent as homozygous at a rate of 0.06%. Actual homozygous prevalence in a sample of 4550 is 0.04%, though it's lower and non-existent in 2000-3000 combined additional samples.

    This one actually shows up in a fair bit of research, which is uncommon for such a rare mutation. That research shows that the mutation isn't associated with ALS, breast cancer, lung cancer, or prostate cancer. One study has this to say:
    Another study found that being heterozygous for the rarer allele reduced the increased risk of developing colorectal cancer (CRC) from eating more red meat, which would suggest that being homozygous would provide the same or more protection:
    Three different modelling programs, which make sophisticated guesses based on a great deal of information, including gene structure and binding sites, all predicted that the mutation is possibly damaging or impactful, or that it would be destabilizing of the protein created. But in that study, the mutant proteins interacted normally with their target.

    So that SNP is a bit tricky. It might be a bit beneficial and not cause problems when heterozygous, and lab experiments of the homozygous version show that it behaves pretty normally. But there's been no real studies of disease or risk association in homozygous people, due to rarity.

    SNPedia is very basic and open to error due to being edited by the general public.

    A good starting point is https://www.ncbi.nlm.nih.gov/projects/SNP. That gives prevalence data, and links to a lot of research. It also shows if the SNP is a missense or nonsense mutation, or located in a splice site. Sometimes mutations are labeled as benign or pathogenic, but those aren't particularly accurate or decisive. scholar.google.com is a good place to find research about a specific mutation, usually by rs number, but sometimes by mutation abbreviation and gene name.

    www.omim.org will list known pathogenic mutations, as well as summarizing a lot of research about the relevant gene, if there is any. www.genecards.org also gives a very good summary of the gene and associated diseases at the top of the page, and a lot of details further down. www.uniprot.org also has a lot of structural data for the gene and protein, but contains more advanced info that is going to be difficult to understand.
     
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  14. tango

    tango Senior Member

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    New Zealand
  15. Sea

    Sea Senior Member

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    Did you miss this bit?
    Update: Since the writing of this article, SourceForge has been sold to a new company that stopped the DevShare program discussed in this article. We’re leaving this article here for historical reference, but it has since stopped these shady practices.
     
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  16. tango

    tango Senior Member

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    Thanks, yes I did miss that. Brain fog ;)

    I will download it in the morning and run my data through it.
     
  17. tango

    tango Senior Member

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    Sorry, brain fogged again. I've downloaded the .db files but I don't know what to do with them to find out which of my genes are in the 1%

    How do I actually run the program? This is what I did:
    1. I downloaded and unzipped the files
    2. I downloaded java
    3. I double clicked genes.h2 and it says it can't find the file associated with it

    4. Update: I associated the file with java but it just flashes open a window and then dies.
    I'm not sure what to do ;)
     
    Last edited: Oct 16, 2017
  18. Sea

    Sea Senior Member

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    Sorry tango, I don't know what to do either. When I had trouble running the program when it was first created Valentijn had me send her my file and ran it through for me. She is not able to respond to you at the moment though because she is currently on moderation.
     
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  19. tango

    tango Senior Member

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    @Sea thanks for the reply

    Someone run my genes through a 1% program and there were nearly 1,000 (apparently 650 is more normal) but I'm not sure if that's the same program.

    Once I have the list of 1% SNPS being measured I will look at creating a Livewello template. That might be easier for people
     
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  20. tango

    tango Senior Member

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    Success! I restarted my PC and tried the genes file again and this time it actually ran.

    I know @Valentijn may not be able to reply but I will post the data here anyway. Feel free to PM me if you have any questions :)


    rs17235668,1,C,0.003,CG,,,,,MTOR,
    rs1057624,1,C,0.010,CC,,,,,MTHFR/C1orf167,Y
    rs35737219,1,A,0.010,AG,,T571M,-1,,MTHFR,
    rs11587313,1,G,0.010,GT,,,,,PADI2,
    rs16798,1,G,0.010,GT,,,,,DPYD,
    rs11125073,2,C,0.010,CT,,,,,
    rs2419643,2,G,0.010,AG,,,,,
    rs11678166,2,A,0.010,AG,,,,,REL,
    rs2860771,2,A,0.010,AG,,,,,
    rs6577014,2,C,0.010,CT,,,,,FAHD2A,
    rs13014679,2,C,0.010,AC,,,,,FER1L5,
    rs12619170,2,C,0.000,AC,,,,,ANKRD36B,
    rs7587534,2,G,0.010,AG,,R1245K,2,,VWA3B,
    rs10496708,2,T,0.010,CT,,,,,
    rs2232346,3,C,0.010,CT,,F262L,0,,IL17RB,
    rs11708449,3,G,0.010,AG,,,,,
    rs2231223,3,A,0.010,AG,,,,,AP2M1,
    rs34577120,3,C,0.010,AC,,,,,PPP1R2,
    rs4130382,4,A,0.010,AG,,,,,PIGG,
    rs6413413,4,A,0.010,AT,,T20S,1,,ADH1B,
    rs12513803,5,A,0.010,AG,,,,,
    rs17302526,5,T,0.010,CT,,,,,TRIO,
    rs1164694,5,G,0.010,AG,,,,,NSA2,
    rs540979,5,T,0.010,CT,,,,,
    rs3846717,5,G,0.010,AG,,,,,APC,
    rs17689328,5,T,0.010,CT,,,,,SLC22A4/LOC553103,
    rs7724670,5,A,0.010,AG,,,,,LOC643201,
    rs17282871,6,A,0.010,AG,,,,,CDYL,
    rs10484333,6,A,0.010,AG,,,,,
    rs9462865,6,C,0.010,CT,,,,,KLHDC3/RRP36,
    rs9401670,6,G,0.010,GT,,,,,TRDN,
    rs17648408,6,T,0.010,CT,,,,,ECHDC1,
    rs1805324,7,T,0.010,CT,,M622I,1,untested,PMS2,
    rs17336988,7,A,0.010,AG,,,,,EGFR,
    rs4986910,7,G,0.003,AG,,M445T,-1,,CYP3A4,
    rs1297632,7,A,0.010,AG,,,,,
    rs4647904,8,A,0.010,AG,,,,,FGFR1,
    rs17666791,10,C,0.010,CT,,,,,MYO3A,
    rs11204267,10,G,0.010,AG,,,,,
    rs12283985,11,T,0.010,CT,,,,,PPFIBP2,
    rs11568482,11,A,0.010,AT,,I216F,0,,SLC22A8,
    rs12802869,11,G,0.010,GT,,,,,
    rs7119270,11,A,0.010,AG,,,,,PAAF1,
    rs12721043,11,A,0.003,AC,,A161S,1,,APOA4,
    rs9332869,11,T,0.010,CT,,,,,
    rs10840932,12,C,0.010,CT,,,,,
    rs11540149,12,T,0.010,CT,,,,,VDR,
    rs682732,12,A,0.010,AC,,,,,PPM1H,
    rs1799954,13,T,0.002,CT,,R2034C,-3,other,BRCA2,
    rs17619183,13,C,0.010,AC,,,,,
    rs3093921,14,G,0.010,AG,,D235G,-1,,PARP2,
    rs17778186,14,A,0.010,AG,,,,,FOXN3,
    rs11629789,15,C,0.010,CT,,,,,CHRM5/AVEN,
    rs4313770,15,T,0.010,GT,,,,,RASGRP1,
    rs6161,15,T,0.001,CT,,E156K,1,,CYP11A1,
    rs17601226,15,C,0.010,CT,,,,,ALPK3,
    rs11466045,16,G,0.010,AG,,D438T,-1,Uncertain significance,MEFV,
    rs8053266,16,T,0.010,CT,,,,,ABCC1,
    rs58073789,16,T,0.010,CT,,R610K,2,,ABCC6,
    rs12920057,16,C,0.010,CT,,,,,
    rs35874481,17,A,0.010,AG,,,,,SCARF1,
    rs8176320,17,T,0.010,CT,,,,,BRCA1,
    rs12945560,17,T,0.010,CT,,,,,MPP3,
    rs28730837,17,A,0.010,AG,,A332V,0,Pathogenic,MPO,
    rs4926123,19,T,0.010,CT,,,,,
    rs17661437,20,A,0.010,AG,,,,,RALGAPA2,
    rs1801122,22,A,0.010,AC,,P550T,-1,,CSF2RB,
    rs13056402,22,T,0.010,CT,,,,,XPNPEP3,
    rs5909140,X,A,0.010,AG,,,,,
    rs5952515,X,T,0.010,GT,,,,,MAGIX,
    rs17301297,X,A,0.010,AG,,,,,ZC4H2,
    rs11798978,X,T,0.010,GT,,,,,NHSL2,
    rs12848140,X,G,0.005,AG,,,,,CAPN6,
    rs6568025,X,C,0.010,CT,,,,,ZCCHC16,
    rs5930575,X,G,0.010,AG,,,,,HS6ST2,
     
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