Open main menu

Genome Analysis Wiki β


Variant classification

2,598 bytes added, 20:44, 25 February 2016
Representation of close by variants
The Variant Call Format (VCF) is a flexible file format specification that allows us to represent many different variant types ranging from SNPs, indels to copy number variations. However, variant representation in VCF is non-unique for variants that have explicitly expressed reference and alternate sequences.
On this wiki page, we describe a a variant classification system for VCF variantsentries that is invariant to [ normalization] except for the case of MNPs.
= Definitions =
The definition of a variant is based on the definition of each allele with respect to the reference sequence. We consider 5 major types loosely defined decribed as follows.
;1. SNP
: The reference and alternate sequences are of length 1 and the base nucleotide is different from one another.
;2. MNP
: a.The reference and alternate sequences are of the same length and have to be greater than 1 and all nucleotides in the sequences differ from one another.
: OR
: b. all All reference and alternate sequences have the same length(this is applicable to all alleles).
: a. The reference and alternate sequence sequences are not of the same length.: AND: b. The removal of a subsequence of the longer sequence would reduce the longer sequence to the smaller sequence.
: a. A clumping of nearby SNPs, MNPs or Indels.
;5. SV
: The alternate sequence is represented by a an angled bracket tag. = Classification Procedure = #Trim each allele with respect to the reference sequence individually#Inspect length, defined as length of alternate allele minus length of reference allele.##if length = 0###if length(ref) = 1 and nucleotides differ, classify as SNP (count ts and tv too)###if length(ref) > 1 ####if all nucleotides differ, classify as MNP (count ts and tv too)####if not all nucleotides differ, classify as CLUMPED (count ts and tv too)##if length <math>\ne</math> 0, classify as INDEL###if shorter allele is of length 1####if shorter allele does not match either of the end nucleotides of the longer allele, add SNP classification ###if shorter allele length > 1####compare the shorter allele sequence with the subsequence in the 5' end of the longer allele (count ts and tv too)#####if all nucleotides differ, add MNP classification#####if not all nucleotides differ, add CLUMPED classification#Variant classification is the union of the classifications of each allele present in the variant.#If all alleles are the same length, add MNP classification.
= Examples =
We present the following examples to explain the concepts explained earlierclassification described.
== Legend for examples ==
ALT T #INDEL, 1 del
#Note that although the padding base differs - A vs T, this is actually a simple indel because it is simply a deletion of a A base.
#If you right align this instead of left aligning, then the padding will be T on both the reference and alternative alleles.
#Simple Indel classification should be invariant whether it is left or right aligned.
#Note that it is ambiguous as to which pairing should be a SNP, as such, the transition or transversion contribution is actually
#not defined. In this case, assuming it is a A/G SNP, we get a transition, but we may also consider this as a T/G SNP which
#is a transversion. In such ambiguous cases, we simply consider the aligned bases after left alignment to get the transition
#and transversion contribution. But please be very clear that this is an ambiguous case. It is better to consider this simply
#as a complex variant.
ALT GTTTC #MNP, CLUMEPDCLUMPED, 2 ts #since all the alleles are of the sample same length, classified as MNP too.
ALT GT #SNP, 1 ts ALT AC #SNP, 1 ts #since all the alleles are of the sample length, classified as MNP too.
ALT GTTTC #CLUMPED, 1 ts, 1 tv ALT ATTTC #SNP, 1 tv, note that we get the SNP after truncating the bases ATTT to reveal a G/C transversion SNP #since all the alleles are of the sample length, classified as MNP too.
ALT CT #SNP, 1 tv ALT AG #MNP, 2 tv ALT GTT #INDEL, 1 ins
ALT CG #MNP|, INDEL, 2 tv, 1 del ALT AG #MNP|, INDEL, 1 ts, 1 tv ALT GTGTG #SNP|, INDEL|, CLUMPED, 1 tv, 1 ins == Structured Variants Examples ==  SV<br> REF G ALT &lt;INS:ME:LINE1&gt; #SV SV<br> REF G ALT &lt;CN4&gt; #SV ALT &lt;CN12&gt; #SV =Interesting Variant Types =  Adjacent Tandem Repeats from lobSTR's tandem repeat finder panel. <br>   20 9538655 <span style="color:#FF0000">ATTTATTTATTTATTTATTTATTTATTTATTTATTTATT</span><span style="color:#0000FF">CATTCATTCATTCATTCATTCATTC </span> <STR>  This can be induced as one record considering only the ATTT repeats 20 9538655 <span style="color:#FF0000">ATTTATTTATTT </span> <span style="color:#FF0000">ATTT </span>  one record with CATT repeats 20 9538695 <span style="color:#0000FF">CATTCATT </span> <span style="color:#0000FF">CATT </span>  one record with a mix of both repeat types 20 9538695 <span style="color:#FF0000">TATT<span style="color:#0000FF">CATTCATT </span> <span style="color:#0000FF">CATT </span> = Representation of close by variants =  1:124001690 TTTCTTT--CAAAAAAAGATAAAAAGGTATTTCATGG TTTCTTTAAAAAAAAAAGATAAAAAGGAATTTCATGG
== Weird Examples == a single complex variant CHROM POS REF ALT 1 124001690 C AAA
== Structured Variants Examples == an Indel and SNP adjacent to one another CHROM POS REF ALT 1 124001689 T TAA 1 124001690 C A
noRepresenting it as a single complex variant enforces that both "indel" and "SNP" are always together. of structural variants : 41217 Representing it as 2 separate variants allows both alleles : 38079 deletion : 13135 &lt;DEL&gt; insertion : 16451 &lt;INS&gt; mobile element : 16253 &lt;INS:ME&gt; ALU : 12513 &lt;INS:ME:ALU&gt; LINE1 : 2911 &lt;INS:ME:LINE1&gt; SVA : 829 &lt;INS:ME:SVA&gt; numt : 198 &lt;INS:MT&gt; duplication : 664 &lt;DUP&gt; inversion : 100 &lt;INV&gt; copy number variation : 7729 &lt;CN4&gt; >=3 alleles : 3138 copy number variation : 3138 &lt;CN4&gt;,&lt;CN8&gt;to segregate independently.
= Output =
3 alleles : 273 (0.89) [537/601]
4 alleles : 3 (1.00) [9/9] <br>
no. of Indel : 6600770 #also referred to as simple Indels
2 alleles : 6285861 (0.88) [2937096/3348765] #ins/del ratio and the respective counts
3 alleles : 280892 (8.72) [503977/57807]
4 alleles : 34 (1.16) [109/94]
>=5 alleles : 4 (0.76) [13/17] <br>
no. of Complex Substitutions : 159298 #equivalent to categories not including simple SNPs, Block Substitutions and Simple Indels
2 alleles : 81508 (0.61) [60312/98113] (0.66) [32479/49029]
3 alleles : 71003 (0.69) [35811/51840] (0.34) [34268/100942]