Joly et al., Human Mutation
1
Supp. Data
Variant evaluation using in silico algorithms
Samples
3927
L1002
H2195
H2195
Align GVGD1
SIFT2
PolyPhen-23
Final interpretation
Class interpretation score interpretation score
interpretation
MSH2, c.2075G>T, p.Gly692Val
C65
high risk
0.00
deletious
1.000 Probably damaging
disease causing
MSH6, c.898C>T, p.Arg300Trp
C65
high risk
0.00
deletious
0.999 Probably damaging
disease causing
MLH1, 313G>A, p.Ala105Thr
C55
high risk
0.00
deletious
1.000 Probably damaging
disease causing
MSH6, c.3482C>T, p.Pro1161Leu C65
high risk
0.00
deletious
1.000 Probably damaging
disease causing
Mutation
1-Align GVGD score interpretation: (http://agvgd.iarc.fr/about.php)
The following classifiers, ordered from most likely to interfere with function to least likely, were used:
GD>=65+Tan (10)x(GV^2.5) => Class C65 <=> most likely
GD>=55+Tan (10)x(GV^2.0) => Class C55
GD>=45+Tan (15)x(GV^1.7) => Class C45
GD>=35+Tan (50)x(GV^1.1) => Class C35
GD>=25+Tan (55)x(GV^0.95) => Class C25
GD>=15+Tan (75)x(GV^0.6) => Class C15
Else (GD<15+Tan (75)x(GV^0.6)) => Class C0 <=> less likely
http://agvgd.iarc.fr/classifiers.php
2-SIFT:
Version:
SIFT Score:
http://www.jcvi.org/
version 4.0.3
Ranges from 0 to 1. The amino acid substitution is predicted damaging is the score is <= 0.05, and tolerated if the score is >
0.05.
3-PolyPhen-2:
Version:
Evaluation:
http://www.mutationtaster.org
2.2.2r398
RULES (connected with logical AND)
score
Substitution type
Substitution site properties:
difference:
properties:
+
1 arbitrary
annotated as a functional site
arbitrary
++
2 arbitrary
annotated as a bond formation site
arbitrary
in a region annotated as
3 arbitrary
PHAT matrix difference
transmembrane
resulting from
in a region predicted as
substitution is negative
4 arbitrary
transmembrane
5 <=0.5
arbitrary
arbitrary
atoms are closer than 3Å to atoms of
6
arbitrary
a ligand
>1.0
atoms are closer than 3Å to atoms of
7
a residue annotated as BINDING,
arbitrary
ACT_SITE, or SITE
change of accessible
8
surface propensity
is >=0.75
with normed accessibility <=15%
change of side chain
9
volume is >=60
change of side chain
10 in the
volume is <=-60
interval
change of accessible
(0.5..1.5]
11
surface propensity
is >=1.0
change of side chain
12
volume is >=80
with normed accessibility <=5%
change of side chain
13
volume is <=-80
in the
change of accessible
14 interval
surface propensity
(1.5..2.0]
is >=1.0
PREDICTION
BASIS
EFFECT
probably damaging
probably damaging
sequence annotation
sequence annotation
functional, functional site (2.2)
structural, bond formation (1.2)
possibly damaging
sequence annotation
possibly damaging
sequence prediction
benign
multiple alignment
functional, functional site,
transmembrane (2.2.2)
probably damaging
structure
functional, functional site, ligand
binding (2.2.3)
probably damaging
structure
functional, functional site,
indirect (2.1)
possibly damaging
structure
possibly damaging
structure
possibly damaging
structure
probably damaging
structure
probably damaging
structure
probably damaging
structure
probably damaging
structure
structural, buried site,
hydrophobicity disruption
(1.1.1)
structural, buried site,
overpacking (1.1.2)
structural, buried site, cavity
creation (1.1.3)
structural, buried site,
hydrophobicity disruption
(1.1.1)
structural, buried site,
overpacking (1.1.2)
structural, buried site, cavity
creation (1.1.3)
structural, buried site,
hydrophobicity disruption
(1.1.1)
Joly et al., Human Mutation
score
difference:
15
16
2
RULES (connected with logical AND)
Substitution type
properties:
change of side chain
volume is >=80
change of side chain
volume is <=-80
Substitution site properties:
PREDICTION
BASIS
probably damaging
structure
probably damaging
structure
17
arbitrary
arbitrary
possibly damaging
structure
18 >2.0
arbitrary
arbitrary
probably damaging
multiple alignment
Source: http://genetics.bwh.harvard.edu/pph/pph_help_text.html
EFFECT
structural, buried site,
overpacking (1.1.2)
structural, buried site, cavity
creation (1.1.3)
structural, buried site, cavity
creation (1.1.3)