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MTHFD1 and Interpretation of 23 & Me Reports

Discussion in 'Genetic Testing and SNPs' started by Journeyman, Jan 3, 2017.

  1. Journeyman

    Journeyman Senior Member

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    Screen Shot 2017-01-04 at 10.22.30 AM.png


    View attachment 19043
    Morning Folks,

    Attached is a screen grab of the MTHFD1 from my 23 & Me 'Browse Raw Data' results.
    The purpose of this post is two fold.
    (1) I want to find out what the MTHFD1 SNP actually means in practical terms (and its significance in folate metabolism etc.) for what I understand is my mutated SNP? and
    (2) I want to confirm that I've got the correct method for interpreting these results that appear when using the 'browse raw data' option of 23 & ME.

    For example where it says 'AG' and then 'Orientation Minus' followed by dbSNP Genotype: CT is the correct interpretation as follows:

    - AG is the result that 23&Me gives for this SNP.
    - 'Orientation Minus' such that 23&Me has labelled this SNP the 'wrong way' such that it should read CT if it was 'Orientation Positive' (correct way round)?
    - 'dbSNP' suggests the unmutated 'default' genotype is CT (which also happens to be what the 23&Me label is when set to 'orientation positive')??

    I look forward to your advice so I can do some productive research into this SNP and what it might mean. Right now I have an inkling that it might relate to how useful vegetables might be as a source of folate for me...

    Regards

    Journeyman
     

    Attached Files:

  2. alicec

    alicec Senior Member

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    23andme shows that there are two possible alleles at this position, A or G. They then report that your result is AG. So you are heterozygous for this SNP.

    23andme doesn't make any comment about which is the ancestral and which is the variant allele. You need to look to other sources to find that out - eg dsSNP.

    23andme always reports in the plus or forward direction.

    dsSNP sometimes reports in the plus orientation and sometimes in the minus. They always indicate which direction is used, so in this case 23andme is telling you that dsSNP is reporting CT in the minus direction for this SNP.

    In other words the two results are in complete accord since A always pairs with T and G with C.

    This still doesn't tell you which is the ancestral and which is the variant allele, nor does it tell you anything about the significance. dsSNP is a good place to start to find that out.

    Here is the entry for that SNP.

    So you can see that C (or G in the orientation used by 23andme) is the ancestral allele.

    You can see that the variant is pretty common - the minor allele frequency (MAF) is 0.3750 in 4,877 genomes.

    The PubMed link will give you research papers that you can look at to evaluate the SNP.

    The clinical significance is listed as other, so you need to look further to find out what that means, but it is not listed as a pathogenic SNP.

    You can see that it is a missense mutation resulting in a change in the enzyme protein - arginine (R) is replaced by glutamine (Q).

    If you look in the map view just below the missense mutation info you will see two little boxes in the vertical band corresponding to the SNP position in the gene. If you hover over these, one will give you a list of publications (though you can find these also in the PubMed link) and the other will give you a link to ClinVar where you will find out what the clinical significance "other" might mean.

    This shows it is a risk factor for neural tube defects, giving links to research and to the OMIM page.

    So there is clear evidence that the SNP can be an issue for pregnant women, but nothing certain about other conditions.

    My notes for this SNP are "protein is thermolabile, activity reduced by 25% +/+; purine synthesis reduced; homozygote assoc with NTD, gastric cancer, schizophrenia, bi-polar; increased requirement choline and methyl folate.

    So +/- would have an even smaller effect and undoubtedly would have no consequences for a healthy person.

    Whether it has any consequence if other things are disrupting folate metabolism is unknown. My take is that it seems wise to ensure you are getting plenty of folate and choline via diet and maybe supplements.
     
    Journeyman, Valentijn and Sea like this.
  3. Sea

    Sea Senior Member

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    23andme has not labelled the snp 'the wrong way'. Forward (positive) and reverse (minus) are simply 2 different ways of reading the same information.

    dbsnp indicates that C and T are the 2 usual possibilities for this snp (in reverse) not that CT is default. People can be CC, CT or TT.

    What are your attached files? They don't open for me on my ipad
     
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  4. Journeyman

    Journeyman Senior Member

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    So to test my understanding in light of this clarification:

    23&Me is reporting this SNP in the forward direction for the default (ancestral) genotype (given dbSNP confirmation that CT (the orientation minus of AG) is the ancestral genotype.?

    Thanks for the further info re: how best to look these SNP's up via pubmed and the personal notes re: protein thermolability etc. .... Seems its not really a SNP of significance unless sometime in the future they're able to recognise some kind of GWAS relationship with other mutated SNP's that create a compounding effect...

    We really are on the frontier of science with SNP understandings.... I hope they can make significant progress in the next few years so we aren't just getting the benefits of the knowledge in our twilight years...

    Regards

    Journeyman
     
  5. Journeyman

    Journeyman Senior Member

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    Morning Sea,

    Having read your post I think my question just posted about whether 23&Me is posting the Ancestral (unmutated) genotype is now answered.... ie: They aren't. They're just stating the possible nucleotide sequences of each of the two slots that make up a zygote.

    As for the attached files I found it very confusing at the time of creating the post and it might have something to do with the fact I'm on a Mac? (perhaps similar to why I just can't get Valentijn's 10% rare genes program to output a working PDF) Either way its just a screenshot of my 23&Me raw data for that MTHFD1 SNP to make it easier for respondents to give suggestions on. The other attachments are the same file uploaded using a different option (that just didn't work and so are nonsense pictures)

    Cheers

    Journeyman
     
    Sea likes this.
  6. alicec

    alicec Senior Member

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    No.

    23and me and dsSNP are saying that there are two possible alleles at the position of this SNP. 23andme, reporting in the plus direction, lists these as AG. dsSNP, reporting in the minus direction, report these as CT.

    They are saying the same thing, the result just depends on which DNA strand was analysed. Since A always pairs with T and G with C, you can always work out the sequence of the opposite strand.

    Neither are saying anything about which of the two possibilities is ancestral and which is the variant.

    All you know from 23andme is that people can be AA, AG or GG. They go on to report that you are AG.

    You need to go to the dsSNP page for the SNP (which I linked) to find out which possibility is ancestral. It is G or C, depending on which orientation you use. A or T is the variant.
     
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  7. Journeyman

    Journeyman Senior Member

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    Yup thanks Alice - I think you've confirmed what I was saying in my reply to Sea earlier today. dbSNP do tend to report the ancestral genotype as the default one in their links for these SNP's don't they? (acknowledging that its not always a given)

    Regards
    Journeyman
     
  8. alicec

    alicec Senior Member

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    They list the possible alleles and say which is ancestral. I'm not sure what you mean about the default genotype.
     
  9. Journeyman

    Journeyman Senior Member

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    I use the term default synonymously with ancestral but to save any confusion I'll probably use ancestral from now on...
    Thanks for your clear advice in this thread. As I re-read it again I can't help but wonder what I was thinking at the time of writing!

    Regards

    Journeyman
     

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