Sequence-based mutation analysis
SNP's
Because the HFE-Gen has no annotated functional site, we can just adress the biochemical changes for each SNP. A change in functionality or stability can not described.
To compare the biochemical properties of the amino acid's, we used the very convenient function of wolfram alpha.
| Mutation | Position | Database | Blosum62 | PAM1 | Pam250 | Physicochemical changes |
|---|---|---|---|---|---|---|
| S/C | 65 | HGMD/dbSNP | -1 | 5 | 3 | There is no change in size and charge, just the polarity changes . |
| I/T | 105 | HGMD/dbSNP | -1 | 11 | 6 | An OH-group is replaced by an ethyl-group which leads so a small change in size and a large change in hydrophobicity. |
| Q/H | 127 | HGMD/dbSNP | 0 | 20 | 7 | Because of the aromatic ring, the flexibility is reduced with a histidine at this position. The polarity and hydrophobicity remain the same. |
| C/Y,S | 282 | HGMD/dbSNP | -2/-1 | 3/11 | 3/7 | In both cases, the hydrophobicity is changed. Cysteine is a nonpolar whereas Serine and Tyrosine are polar amino acids. |
| R/M | 330 | HGMD | -1 | 1 | 1 | |
| A/V | 176 | HGMD | 0 | 13 | 9 | |
| R/S | 6 | HGMD | -1 | 11 | 6 | |
| T/I | 217 | dbSNP | -1 | 7 | 4 | |
| M/T | 35 | dbSNP | -1 | 6 | 5 | |
| R/M | 58 | dbSNP | -1 | 1 | 1 |
A change in polarity is just important for residues at the surface of the protein, because with a change in polarity, the hydrophobicity changes and so the water solubility decreases/increases.
SIFT
The prediction of SIFT is marked with a low confidence warning because, the sequences used for the prediction were not diverse enough.
| Mutation | Position | Prediction | Score | Cause disease |
|---|---|---|---|---|
| S/C | 65 | AFFECT PROTEIN FUNCTION | 0.00 | yes |
| I/T | 105 | AFFECT PROTEIN FUNCTION | 0.00 | yes |
| Q/H | 127 | TOLERATED | 0.16 | yes |
| C/Y,S | 282 | AFFECT PROTEIN FUNCTION | 0.00 | yes |
| R/M | 330 | TOLERATED | 0.06 | yes |
| A/V | 176 | AFFECT PROTEIN FUNCTION | 0.01 | yes |
| R/S | 6 | AFFECT PROTEIN FUNCTION | 0.01 | yes |
| T/I | 217 | TOLERATED | 1.00 | |
| M/T | 35 | TOLERATED | 1.00 | |
| R/M | 58 | AFFECT PROTEIN FUNCTION | 0.00 |
The complete prediction for each position and amino acid can be found here
We got three warning messages form SIFT for which we have no explanation at this time.
WARNING: Original amino acid H at position 31 is not allowed by the prediction. WARNING: Original amino acid S at position 45 is not allowed by the prediction. WARNING: Original amino acid Y at position 230 is not allowed by the prediction.
PolyPhen-2
| Mutation | Position | Prediction | Score | Cause disease |
|---|---|---|---|---|
| S/C | 65 | PROBABLY DAMAGING | 0.997 | yes |
| I/T | 105 | PROBABLY DAMAGING | 0.998 | yes |
| Q/H | 127 | BENIGN | 0.002 | yes |
| C/Y,S | 282 | PROBABLY DAMAGING | 1.000/0.997 | yes |
| R/M | 330 | PROBABLY DAMAGING | 0.948 | yes |
| A/V | 176 | PROBABLY DAMAGING | 0.998 | yes |
| R/S | 6 | PROBABLY DAMAGING | 0.738 | yes |
| T/I | 217 | BENIGN | 0.195 | |
| M/T | 35 | PROBABLY DAMAGING | 0.989 | |
| R/M | 58 | PROBABLY DAMAGING | 0.998 |
