Task 8 (MSUD)

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Results

Lab journal

Selected mutations

Following are the selected mutations from HGMD and dbSNP. Changes in physicochemical properties, secondary structures, amino acid substitution scores, conservation and prediction results of different programs are also shown in the table:

mutation physicochemical.changes secondary.structure BLOSUM62.score PAM250.score PSSM.conservation.WT PSSM.conservation.mutant MSA.conservation.WT MSA.conservation.mutant SIFT Polyphen2 MutationTaster SNAP DB
P38H small/fixed conformation/apolar to large/aromatic/polar - -2 0 31 0 0.29 0 tolerated benign NA NA dbSNP
M82L sulfur-containing to aliphatic/branched E 2 4 12 59 0.36 0.01 tolerated benign NA NA dbSNP
T151M small/polar to apolar/sulfur-containing - -1 -1 8 0 0.8 0 tolerated probably/possibly damaging NA NA HGMD
A222T apolar to polar H 0 1 64 4 0.38 0 affect protein function probably damaging NA NA dbSNP
C264W small/sulfur-containing to large/aromatic E -2 -8 52 0 0.91 0 affect protein function probably/possibly damaging NA NA HGMD
R265W positively-charged to aromatic/larger E -3 2 12 0 0.36 0.38 affect protein function probably damaging NA NA HGMD
R314Q guanidin/large/positively-charged to amin H 1 1 23 0 0.35 0 affect protein function probably damaging NA NA dbSNP
R346H hydrophilic to hydrophobic/aromatic - 0 2 92 0 0.9 0 affect protein function probably damaging NA NA HGMD
I361V smaller H 3 4 64 10 0.89 0.01 tolerated benign/possibly damaging NA NA dbSNP
Y413H uncharged to positively-charged - 2 0 74 1 0.9 0 affect protein function probably damaging NA NA HGMD

SIFT

The following table shows the prediction of mutation effects by SIFT. 6 out of 10 mutations are predicted to affect protein function.


mutation prediction score median sequence conservation sequences represented at position
P38H tolerated 0.16 3.16 17
M82L tolerated 0.56 3.03 43
T151M tolerated 0.05 3.03 46
A222T affect protein function 0.04 3.03 46
C264W affect protein function 0.00 3.03 46
R265W affect protein function 0.00 3.03 46
R314Q affect protein function 0.01 3.03 46
R346H affect protein function 0.00 3.03 46
I361V tolerated 0.12 3.03 46
Y413H affect protein function 0.00 3.03 46


Polyphen2

The prediction resuls of Polyphen2 are shown in the following table. 7 out of 10 mutations are predicted to be probably damaging (at least for the trained set HumDiv). For the mutation T151M, this does not agree with the results of SIFT. But for this mutations the Polyphen scores are also the lowest of all mutations that are predicted to be damaging. So Polyphen sees an uncertainty for this mutation too, if it is damaging.


HumDiv HumVar
mutation prediction score sensitivity specificity prediction score sensitivity specificity
P38H benign 0.118 0.93 0.96 benign 0.042 0.93 0.62
M82L benign 0.002 0.99 0.30 benign 0.006 0.97 0.45
T151M probably damaging 0.963 0.78 0.95 possibly damaging 0.622 0.80 0.85
A222T probably damaging 1.000 0.00 1.00 probably damaging 0.943 0.65 0.91
C264W probably damaging 0.989 0.72 0.97 possibly damaging 0.887 0.71 0.89
R265W probably damaging 1.000 0.00 1.00 probably damaging 1.000 0.00 1.00
R314Q probably damaging 1.000 0.00 1.00 probably damaging 0.998 0.18 0.98
R346H probably damaging 1.000 0.00 1.00 probably damaging 0.993 0.47 0.96
I361V benign 0.386 0.90 0.89 possibly damaging 0.610 0.80 0.83
Y413H probably damaging 1.000 0.00 1.0 probably damaging 0.999 0.09 0.99

MutationTaster

SNAP

Summary

Discussion