Variation exercises


Exercise 1 — Human population genetics and phenotype data

The SNP rs1738074 in the 5’ UTR of the human TAGAP gene has been identified as a genetic risk factor for a few diseases.

(a) In which transcripts is this SNP found?

(b) What is the least frequent genotype for this SNP in the Yoruba (YRI) population from the 1000 Genomes phase 3?

(c) What is the ancestral allele? Is it conserved in the 53 eutherian mammals?

(d) With which diseases is this SNP associated? Are there any known risk (or associated) alleles?


Exercise 2 — Exploring a SNP in human

The missense variation rs1801133 in the human MTHFR gene has been linked to elevated levels of homocysteine, an amino acid whose plasma concentration seems to be associated with the risk of cardiovascular diseases, neural tube defects, and loss of cognitive function. This SNP is also referred to as ‘A222V’, ‘Ala222Val’, as well as other HGVS names.

(a) Find the page with information for rs1801133.

(b) Is rs1801133 a Missense variation in all transcripts of the MTHFR gene?

(c) Why are the alleles for this variation in Ensembl given as G/A and not as C/T, as in dbSNP and literature?


(d) What is the major allele in rs1801133?

(e) In which paper(s) is the association between rs1801133 and homocysteine levels described?

(f) According to the data imported from dbSNP, the ancestral allele for rs1801133 is G. Ancestral alleles in dbSNP are based on a comparison between human and chimp. Does the sequence at this same position in other primates confirm that the ancestral allele is G?


Exercise 3 — Exploring a SNP in mouse

Madsen et al in the paper ‘Altered metabolic signature in pre-diabetic NOD mice’ (PloS One. 2012; 7(4): e35445) have described several regulatory and coding SNPs, some of them in genes residing within the previously defined insulin dependent diabetes (IDD) regions. The authors describe that one of the identified SNPs in the murine Xdh  gene (rs29522348) would lead to an amino acid substitution and could be damaging as predicted as by SIFT (

(a) Where is the SNP located (chromosome and coordinates)?

(b) What is the HGVS recommendation nomenclature for this SNP?

(c) Why does Ensembl put the C allele first (C/T)?

(d) Are there differences between the genotypes reported in NOD/LTJ and BALB/cByJ, according to the PERLGEN panel?


Exercise 4 — The VEP

Resequencing of the genomic region of the human CFTR (cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7) gene (ENSG00000001626) has revealed the following variants (alleles defined in the forward strand):

  • G/A at 7: 117,530,985

  • T/C at 7: 117,531,038

  • T/C at 7: 117,531,068

Use the VEP tool in Ensembl and choose the options to see SIFT and PolyPhen predictions. Do these variants result in a change in the proteins encoded by any of the Ensembl genes? Which gene? Have the variants already been found?