Tool
|
Score
|
Reference range
|
Implications
|
NC_000004.12(NM_001371596.2):c.638C>A* (MFSD8 gene; p.Pro213Gln; Novel variant)
|
CADD PHRED
|
24.7
|
Pathogenic variants with PHRED score < 30
|
Pro213Gln (P213Q) variant is highly conserved and it falls into the active transporter motif
(PF00083), whose sensitivity to deleterious variants is reasonably high. Protein structure and clinical relevance-based prediction scores showed that Pro213Gln led to significant alteration in the protein function with disease-relevant impact.
Finally, the predicted mechanism of action is that Pro213Gln might lead to transporter dysfunction for accumulating harmful compounds.
|
SIFT
|
Deleterious (0.03)
|
A SIFT score of less than 0.05 is predicted to be deleterious.
|
PolyPhen
|
HumDiv= 0.994 with Sensitivity (TPR)= 0.69; specificity (TNR): 0.97
HumVar=0.822 with Sensitivity (TPR)= 0.74; specificity (TNR): 0.88
|
(0.0 to 0.15) predicted to be benign. (0.15 to 1.0) possibly damaging. (0.85 to 1.0) more confidently predicted to be damaging.
|
BLOSUM62
|
-1 (Conserved)
|
Typically +1 or +5 for matches, and -1 or -4 for mismatches
|
phastCons30way mammalian including human
|
0.992
Highly conserved
|
Ranged from 0-1; higher score means highly conserved
|
ClinPred (score)
|
Deleterious (0.982)
|
Ranged from 0-1; higher score is likely to be pathogenic
|
DEOGEN2 (score)
|
Deleterious (0.699) representing PFAM log-odd score (PF) = 26.7, and LOR (Log-Odd Ratio) = 22%.
Similarity between Prolin (Pro) and Glutamone (Gln) = 49.5%, where the charge similarity is lesser =7.14% of 49.5% )
|
Ranged from 0-1; higher score is likely to be pathogenic with cutoff=0.5
|
MutPred score; based on Q8NHS3-1_human.
|
0.841
Altered Transmembrane protein (pvalue = 2.1e-04)
|
It was estimated that a pathogenicity threshold of 0.68 yields a false positive rate of 10% and that of 0.80 yields a false positive rate of 5%.
|
PROVEAN score
|
-3.12
|
Ranged from -14 to 14, the smaller
score is likely has damaging effect. Cutoff for PROVEAN scores was set to −2.5 for high balanced accuracy
|
VEST4 score
|
0.937
|
Range from 0 to 1, the highest score causes functional change
|
MUpro**
|
∆∆G = -0.626 (DECREASE stability with high confidence)
|
Above zero is increase stability, while less zero is decrease stability
|
BayesDel
|
Deleterious (Supporting) = 0.23
|
Ranged from -1.29334 to 0.75731. cutoff between deleterious (D) and tolerated (T) is -0.0570105. Based on ClinGen’s recommendation, score above 0.5 corresponds with Strong pathogenic evidence, score in the range (0.27, 0.5) Moderate pathognic, score in the range (0.13, 0.27 ) Supporting pathognic , score in the range (-0.36 ,-0.18) Supporting benign, and score below-0.18 Moderate benign.
|
GenoCanyon
|
Deleterious (1(
|
Range from 0 to 1, the highest score is deleterious
|
fitCons
|
Deleterious (0.7)
|
Range from 0 to 1, the highest score score is deleterious
|
UniProt mining
|
Subcellular location; Helical transmembrane (212-232)
|
|
MotifFinder (In Pfam database)
|
MFS_1 (42-359)
PF07690, Major Facilitator Superfamily
E-value 1.1e-06
Sugar_tr (71-229)
PF00083, Sugar (and other) transporter
E-value 9.5e-11)
|
|
NC_000005.10(NM_018928.3):c.1463C>T (PCDHGC4; p.Ala488Val; Reported variant; rs775104626) ClinVar; pathogenic, and citation = 0
|
CADD PHRED
|
24.4
|
Pathogenic variants with PHRED score < 30
|
Ala488Val (A488V) variant is highly conserved and it falls into the active domain called Codherin domain (PRU00043) that is responsible for cell-cell adhesion. Therefore, sensitivity to deleterious variants is reasonably high. Clinical relevance-based prediction score showed that Ala488Val has disease-relevant impact.
Finally, the predicted mechanism of action is that Ala488Val might contribute in cell adhesion dysfunction.
|
SIFT
|
0
|
A SIFT score of less than 0.05 is predicted to be deleterious.
|
PolyPhen
|
HumDiv=0.99 with sensitivity (TPR)= 0.14; specificity (TNR)= 0.99
HumVar= 0.97 with sensitivity (TPR)= 0.60; specificity (TNR)= 0.93
|
(0.0 to 0.15) predicted to be benign. (0.15 to 1.0) possibly damaging. (0.85 to 1.0) more confidently predicted to be damaging.
|
phastCons30way mammalian including human
|
0.974
Highly conserved
|
Ranged from 0-1; higher score means highly conserved
|
ClinPred (score)
|
D (0.974)
|
Ranged from 0-1; higher score is likely to be pathogenic
|
PROVEAN score
|
-3.55
|
Ranged from -14 to 14, the smaller
score is likely has damaging effect. Cutoff for PROVEAN scores was set to −2.5 for high balanced accuracy
|
MUpro*
|
∆∆G = -0.4 (DECREASE stability, with moderate confidence)
|
Above zero is increase stability, while less zero is decrease stability
|
UniProt mining
|
Located in Codherin 5 domain PRU00043
|
|
NC_000009.12(NM_001195248.2):c.635G>T (APTX; p.Ser212Ile; Novel variant)
|
CADD PHRED
|
23.5
|
Pathogenic variants with PHRED score < 30
|
Ser212Ile (S212I) variant is highly conserved and it falls into the active Histidine triad (HIT) domain, whose sensitivity to deleterious variants is reasonably high.
HIT domain serve as catabolic enzymes acting on nucleotide‐containing substrates, where it is part of binding loop for the alpha-phosphate of purine mononucleotide
Hydrophobicity and solvent accessibility are most chemical properties contributors in Ser212Ile pathogenicity.
Finally, the predicted mechanism of action is that Ser212Ile might lead to binding dysfunction with alpha-phosphate containing purine mononucleotide.
|
SIFT
|
0
|
A SIFT score of less than 0.05 is predicted to be deleterious.
|
PolyPhen
|
HumDiv= 0.880 with Sensitivity (TPR)= 0.68; specificity (TNR): 0.95
HumVar=0.878 with Sensitivity (TPR)= 0.73; specificity (TNR): 0.87
|
(0.0 to 0.15) predicted to be benign. (0.15 to 1.0) possibly damaging. (0.85 to 1.0) more confidently predicted to be damaging.
|
phastCons30way mammalian including human
|
0.986
Highly conserved
|
Ranged from 0-1; higher score means highly conserved
|
BLOSUM62
|
-2 (Conserved)
|
Typically +1 or +5 for matches, and -1 or -4 for mismatches
|
FATHMM (score)
|
D (-4.04(
|
|
ClinPred (score)
|
D (0.982)
|
Ranged from 0-1; higher score is likely to be pathogenic
|
DEOGEN2 (score)
|
Deleterious (0.91) representing PFAM log-odd score (PF) = 27.4, and LOR (Log-Odd Ratio) = 19.7%.
SNPMuSiC score= 0.43
Hydrophobicity; Ser= -0.80 / Ile= 4.50
Residue Solvent accessibility; Ser= 227.8 / Ile= 272.6
Side chain Solvent accessibility; Ser= 86.34 / Ile= 140.9
|
Ranged from 0-1; higher score is likely to be pathogenic with cutoff=0.5
The obtained SNPMuSiC score indicates that it is deleterious the solvent accessibility of the wild-type residue is 2.62% which means that the residue is buried and mutant residue is exposed
|
Hydrogen bonding capacity
|
(For Ser); with LYS214 and ALA215
(For Ile); with ALA215
|
|
PROVEAN score
|
-4.89
|
Ranged from -14 to 14, the smaller score is likely has damaging effect. Cutoff for PROVEAN scores was set to −2.5 for high balanced accuracy
|
VEST4 score
|
0.616
|
Range from 0 to 1, the highest score causes functional change
|
Revel
|
Deleterious (Moderate) (0.83)
|
Based on ClinGen’s recommendation, score above 0.932 corresponds with Strong pathogenic evidence, score in the range (0.773, 0.932) Moderate pathognic, score in the range (0.644, 0.773) Supporting pathognic , score in the range (0.183 ,0.29) Supporting benign, score in the range (0.016, 0.183) Moderate benign, score in the range (0.003, 0.016) Strong benign, and score below 0.003 Very Strong benign.
|
Varity
|
Deleterious (0.94)
|
Score ranges between 0 to 1. Scores less than 0.1 have probability of 0.9 being benign, score of 0.35 has about an equal probability for being benign or deleterious (VUS), score of 0.5 hs a probability of 0.7 of being deleterious, and score of 0.55 a probability of 0.8 being deleterious.
|
UniProt mining
|
HIT (Histidine triad ( domain (182-287)
PROSITE; PS51084; HIT_2
|
|
BayesDel
Deleterious
|
(Supporting) (0.25)
|
The range of the score is from -1.29334 to 0.75731. The higher the score, the more likely the variant is pathogenic
|
fitCons
|
Deleterious (0.71)
|
Ranged from 0 to 1, the highest score score is deleterious
|
MetaLR
|
D (0.9313(
|
Ranged from 0 to 1, higher score is likely to be pathogenic
|
NC_000009.12(NM_001330701.2):c.2650G>C (AGTPBP1; p.Gly884Arg; Novel variant)
REPORTED PREVIOUSLY AS (NM_001330701.2:c.2650G>A; p.Gly884Arg) with ClinVar= NA, and citation=0
|
CADD PHRED
|
23.5
|
Pathogenic variants with PHRED score < 30
|
Gly884Arg (G884R) variant is highly conserved and it falls into crucial loop region for protein structure stabilization. Therefore, sensitivity to deleterious variants is reasonably high.
Protein structure and clinical relevance-based prediction scores showed that Gly884Arg led to significant alteration in the bonding capacity with disease-relevant impact.
Finally, the predicted mechanism of action is that Gly884Arg might lead to altered protein conformation inhibiting deglutamylation of tubulin and non-tubulin target proteins.
|
SIFT
|
0
|
A SIFT score of less than 0.05 is predicted to be deleterious.
|
PolyPhen
|
HumDiv= 1 with Sensitivity (TPR)= 0.80; specificity (TNR): 0.98
HumVar=0.998 with Sensitivity (TPR)= 0.81; specificity (TNR): 0.95
|
(0.0 to 0.15) predicted to be benign. (0.15 to 1.0) possibly damaging. (0.85 to 1.0) more confidently predicted to be damaging.
|
phastCons30way mammalian including human
|
0.999
Highly conserved
|
Ranged from 0-1; higher score means highly conserved
|
BLOSUM62
|
-2 (Conserved)
|
Typically +1 or +5 for matches, and -1 or -4 for mismatches
|
ClinPred (score)
|
D (0.998)
|
Ranged from 0-1; higher score is likely to be pathogenic
|
MutPred score; based on Q9UPW5-1 human
|
0.787
Loss of Loop (P = 0.05); Altered Transmembrane protein (P = 8.3e-03)
|
It was estimated that a pathogenicity threshold of 0.68 yields a false positive rate of 10% and that of 0.80 yields a false positive rate of 5%.
|
Hydrogen bonding capacity
|
(For Arg); with LYS638
(For Ile); with LYS638
|
|
Hydrophobic bonding capacity
|
(For Arg); with LYS638
(For Ile); Null
|
|
PROVEAN score
|
-6.75
|
Ranged from -14 to 14, the smaller score is likely has damaging effect. Cutoff for PROVEAN scores was set to −2.5 for high balanced accuracy
|
VEST4 score
|
0.862
|
Range from 0 to 1, the highest score causes functional change
|
Varity
|
Deleterious (0.84)
|
Range from 0 to 1, the highest score is deleterious
|
GenoCanyon
|
Deleterious (1)
|
Range from 0 to 1, the highest score is deleterious
|
fitCons
|
Deleterious (0.71)
|
Range from 0 to 1, the highest score is deleterious
|
NC_000011.10(NM_000391.4: c.1145+2T>G (TPP1; c.1145+2T>G; Reported variant; COSV100196937) ; splice_donor_variant (Int. 9)
|
MaxEntScan
|
Ref= 10.858
Alt=3.211
Diff=7.647
|
to diminish splicing (diff > 0)
high (alt < 6.2), moderate (6.2 alt 8.5) or low (alt > 8.5) potential of disrupting native splice sites
|
This variant has reasonable potential effect to diminish the splicing donor site to be skipped, thus alternative non-functional isoforms might be produced
|
BayesDel
|
Deleterious (Strong) (0.66)
|
The range of the score is from -1.29334 to 0.75731. The higher the score, the more likely the variant is pathogenic
|
SpliceAI
|
Splice-Altering = 0.99
|
ranged from 0 to 1 and can be interpreted as the probability of the variant being splice-altering
|
dbscSNV Ada
|
Deleterious (1)
|
The score can range from 0 to 1, when higher values are more likely of being deleterious.
|
dbscSNV RF
|
Deleterious (0.92)
|
The score can range from 0 to 1, when higher values are more likely of being deleterious.
|
GenoCanyon
|
Deleterious (1)
|
The score can range from 0 to 1, when higher values are more likely of being deleterious.
|
NC_000009.12(NM_001330701.2):c.1378A>G ( AGTPBP1; p.Thr460Ala; reported variant rs1375829417) ClinVar; NA, and citation= 0
|
CADD PHRED
|
24.2
|
Pathogenic variants with PHRED score < 30
|
Thr460Ala (T460A) variant is highly conserved with decreasing impact on the protein stability. However, it isn't falls into known motifs or domains. Therefore, sensitivity to deleterious variants is reasonably accepted.
Finally, the predicted mechanism of action is that Thr460Ala might lead to altered the protein stability. Hence, the degradable effect is predicted.
|
SIFT
|
0.03
|
A SIFT score of less than 0.05 is predicted to be deleterious.
|
PolyPhen
|
HumDiv= 0.842 with Sensitivity (TPR)= 0.83; specificity (TNR): 0.93
|
(0.0 to 0.15) predicted to be benign. (0.15 to 1.0) possibly damaging. (0.85 to 1.0) more confidently predicted to be damaging.
|
phastCons30way mammalian including human
|
0.962
Highly conserved
|
Ranged from 0-1; higher score means highly conserved
|
MutPred score; based on Q9UPW5-1 human
|
0.372
Conserved
|
It was estimated that a pathogenicity threshold of 0.68 yields a false positive rate of 10% and that of 0.80 yields a false positive rate of 5%.
|
GenoCanyon
|
Deleterious (1)
|
Range from 0 to 1, the highest score is deleterious
|
fitCons
|
Deleterious (0.73)
|
Range from 0 to 1, the highest score is deleterious
|
MUpro*
|
∆∆G = -0.57 (DECREASE stability with high confidence)
|
Above zero is increase stability, while less zero is decrease stability
|