In-silico Analysis of NF1 Missense Variants in ClinVar: Translating Variant Predictions into Variant Interpretation and Classification
Abstract
:1. Introduction
2. Results
2.1. VEST3, REVEL and ClinPred Prediction Score Distribution for NF1 Missense Variants
2.2. Development of a Classifier for Classification Fine-Tuning
2.3. Reclassification Results after Training
3. Discussion
4. Materials and Methods
4.1. Dataset of Missense Variants
4.2. Statistical Analyses
4.3. Five Model Classification
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
NGS | Next Generation Sequencing |
DCG | Disease-causing gene |
ACMG | American College of Medical Genetics |
AMP | Association for Molecular Pathology |
VUS | Variant of uncertain significance |
NF1 | Neurofibromatosis type 1 |
GAP | GTPase activating protein |
CI | Variant with Conflicting Interpretation |
LOVD | Leiden Open Variation Database |
HGMD | Human Gene Mutation Database |
References
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VEST3 | REVEL | ClinPred | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
LB | VUS | CI | LP | LB | VUS | CI | LP | LB | VUS | CI | LP | |
Number of Values | 49 | 1363 | 50 | 122 | 49 | 1360 | 50 | 122 | 48 | 1364 | 50 | 122 |
Minimum | 0.02 | 0.067 | 0.09 | 0.347 | 0.038 | 0.018 | 0.021 | 0.026 | 0.005 | 0.019 | 0.004 | 0.596 |
25% Percentile | 0.2435 | 0.584 | 0.434 | 0.8728 | 0.1145 | 0.2103 | 0.1585 | 0.5203 | 0.1318 | 0.6915 | 0.124 | 0.9828 |
Median | 0.528 | 0.77 | 0.707 | 0.948 | 0.216 | 0.381 | 0.274 | 0.7395 | 0.394 | 0.914 | 0.4035 | 0.993 |
75% Percentile | 0.742 | 0.885 | 0.9558 | 0.989 | 0.365 | 0.645 | 0.683 | 0.8848 | 0.944 | 0.9810 | 0.9823 | 0.998 |
Maximum | 0.978 | 1.000 | 0.998 | 0.9990 | 0.785 | 0.987 | 0.909 | 0.9890 | 0.998 | 1.000 | 1.000 | 1.000 |
95% CI of Median | ||||||||||||
Actual Confidence Level | 95.56% | 95.00% | 96.72% | 96.31% | 95.56% | 95.00% | 96.72% | 96.31% | 97.07% | 95.00% | 96.72% | 96.31% |
Lower Confidence Limit | 0.423 | 0.755 | 0.558 | 0.936 | 0.168 | 0.356 | 0.216 | 0.681 | 0.176 | 0.905 | 0.156 | 0.991 |
Upper Confidence Limit | 0.67 | 0.783 | 0.815 | 0.972 | 0.298 | 0.401 | 0.494 | 0.809 | 0.828 | 0.927 | 0.889 | 0.995 |
Coefficient of Variation | 51.5% | 32.39% | 43.51% | 12.93% | 73.59% | 60.89% | 72.6% | 34.83% | 78.04% | 31.97% | 80.05% | 6.651% |
Medians Difference | Adjusted p Value | ||
---|---|---|---|
VEST3 | LEANING BENIGN vs. VUS | −0.242 | <0.0001 |
LEANING BENIGN vs. CI | −0.179 | 0.0022 | |
LEANING BENIGN vs. LEANING PATHOGENIC | −0.42 | <0.0001 | |
VUS vs. CI | 0.063 | 0.578 | |
VUS vs. LEANING PATHOGENIC | −0.178 | <0.0001 | |
CI vs. LEANING PATHOGENIC | −0.241 | <0.0001 | |
REVEL | LEANING BENIGN vs. VUS | −0.165 | <0.0001 |
LEANING BENIGN vs. CI | −0.058 | 0.0284 | |
LEANING BENIGN vs. LEANING PATHOGENIC | −0.5235 | <0.0001 | |
VUS vs. CI | 0.107 | 0.3313 | |
VUS vs. LEANING PATHOGENIC | −0.3585 | <0.0001 | |
CI vs. LEANING PATHOGENIC | −0.4655 | <0.0001 | |
ClinPred | LEANING BENIGN vs. VUS | −0.52 | <0.0001 |
LEANING BENIGN vs. CI | −0.0095 | 0.3826 | |
LEANING BENIGN vs. LEANING PATHOGENIC | −0.599 | 0.0004 | |
VUS vs. CI | 0.5105 | <0.0001 | |
VUS vs. LEANING PATHOGENIC | −0.079 | <0.0001 | |
CI vs. LEANING PATHOGENIC | −0.59 | <0.0001 |
VEST3 Scores Score Comparison INTER DOMAINS | Median Difference | Adjusted p Value |
---|---|---|
RAS-GAP vs. CRAL-TRIO | 0.133 | <0.0001 |
RAS-GAP vs. PH LIKE | 0.061 | 0.1102 |
RAS-GAP vs. ARMADILLO | 0.126 | <0.0001 |
RAS-GAP vs. NO FUNCTION | 0.1595 | <0.0001 |
CRAL-TRIO vs. PH LIKE | −0.072 | 0.0498 |
CRAL-TRIO vs. ARMADILLO | −0.007 | 0.7220 |
CRAL-TRIO vs. NO FUNCTION | 0.0265 | 0.3105 |
PH LIKE vs. ARMADILLO | 0.065 | 0.0405 |
PH LIKE vs. NO FUNCTION | 0.0985 | 0.0009 |
ARMADILLO vs. NO FUNCTION | 0.0335 | 0.0174 |
REVEL Scores Score Comparison INTER DOMAINS | Median Difference | p Value |
RAS-GAP vs. CRAL-TRIO | 0.3435 | <0.0001 |
RAS-GAP vs. PH LIKE | 0.0365 | 0.1087 |
RAS-GAP vs. ARMADILLO | 0.3695 | <0.0001 |
RAS-GAP vs. NO FUNCTION | 0.3445 | <0.0001 |
CRAL-TRIO vs. PH LIKE | −0.307 | 0.0001 |
CRAL-TRIO vs. ARMADILLO | 0.026 | 0.5751 |
CRAL-TRIO vs. NO FUNCTION | 0.001 | 0.3637 |
PH LIKE vs. ARMADILLO | 0.333 | <0.0001 |
PH LIKE vs. NO FUNCTION | 0.308 | <0.0001 |
ARMADILLO vs. NO FUNCTION | −0.025 | 0.4453 |
ClinPred Scores Score Comparison INTER DOMAINS | Median Difference | p Value |
RAS-GAP vs. CRAL-TRIO | 0.0365 | 0.013 |
RAS-GAP vs. PH LIKE | 0.056 | 0.066 |
RAS-GAP vs. ARMADILLO | 0.03 | 0.0002 |
RAS-GAP vs. NO FUNCTION | 0.101 | <0.0001 |
CRAL-TRIO vs. PH LIKE | 0.0195 | 0.8558 |
CRAL-TRIO vs. ARMADILLO | −0.0065 | 0.8558 |
CRAL-TRIO vs. NO FUNCTION | 0.0645 | 0.0283 |
PH LIKE vs. ARMADILLO | −0.026 | 0.8558 |
PH LIKE vs. NO FUNCTION | 0.045 | 0.0253 |
ARMADILLO vs. NO FUNCTION | 0.071 | <0.0001 |
METAPREDICTOR | Variant Classification at ClinVar | # of Variants Reclassified as Leaning Benign | # of Variants Reclassified as VOUS | # of Variants Reclassified as Leaning Pathogenic |
---|---|---|---|---|
VEST3 | B, LB, B/LB | 20 | 24 | 5 |
VUS | 251 | 641 | 471 | |
CI | 14 | 19 | 17 | |
LP, LP/P, P | 1 | 23 | 98 | |
TOTAL | 286 | 707 | 591 | |
REVEL | B, LB, B/LB | 23 | 21 | 5 |
VUS | 322 | 644 | 394 | |
CI | 17 | 19 | 14 | |
LP, LP/P, P | 6 | 33 | 83 | |
TOTAL | 368 | 717 | 496 | |
CLINPRED | B, LB, B/LB | 23 | 14 | 11 |
VUS | 136 | 659 | 569 | |
CI | 24 | 12 | 14 | |
LP, LP/P, P | 0 | 18 | 104 | |
TOTAL | 183 | 703 | 698 |
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Accetturo, M.; Bartolomeo, N.; Stella, A. In-silico Analysis of NF1 Missense Variants in ClinVar: Translating Variant Predictions into Variant Interpretation and Classification. Int. J. Mol. Sci. 2020, 21, 721. https://doi.org/10.3390/ijms21030721
Accetturo M, Bartolomeo N, Stella A. In-silico Analysis of NF1 Missense Variants in ClinVar: Translating Variant Predictions into Variant Interpretation and Classification. International Journal of Molecular Sciences. 2020; 21(3):721. https://doi.org/10.3390/ijms21030721
Chicago/Turabian StyleAccetturo, Matteo, Nicola Bartolomeo, and Alessandro Stella. 2020. "In-silico Analysis of NF1 Missense Variants in ClinVar: Translating Variant Predictions into Variant Interpretation and Classification" International Journal of Molecular Sciences 21, no. 3: 721. https://doi.org/10.3390/ijms21030721