nileshhanotia/mutation-predictor-v4

MutationPredictor-CNN v4

Overview

MutationPredictor-CNN v4 is a sequence-based convolutional neural network designed to predict pathogenicity of genomic variants with splice-awareness.

The model uses:

• 401 bp genomic window (GRCh38)
• One-hot encoded forward and reverse complement sequence
• Positional encoding
• Canonical splice motif features (GT/AG)
• Explicit mutation type encoding (12 SNV classes)
• Auxiliary region and splice feature embeddings

This model is trained on ClinVar-derived labeled splice-impact variants.

---

Architecture

Input Features:

• 11-channel sequence encoding
• 12-dim mutation one-hot encoding
• 2-dim region embedding
• 3-dim splice embedding

Model:

Conv1d(11 → 64, kernel=7)
Conv1d(64 → 128, kernel=5)
Conv1d(128 → 256, kernel=3)
AdaptiveAvgPool1d(1)

Fully connected layers:

• 312 → 128
• 128 → 64
• 64 → 1 (logit output)

Activation: ReLU
Regularization: Dropout(0.3)
Loss: BCEWithLogitsLoss

---

Training Details

• Genome build: GRCh38
• Window size: 401 bp
• Optimizer: Adam
• Learning rate: 0.001
• Epochs: 30
• Batch size: 256

Best model selected by highest training AUC.

---

Evaluation

Internal (ClinVar-derived)

AUC ≈ 0.97

External Benchmark – SpliceAI Comparison (1000 variants)

AUC ≈ 0.91

Strict Fair Benchmark (134 variants not seen in training context)

AUC ≈ 0.54

Fair Benchmark by Consequence

Variant Type	Count	AUC
Splice Donor	37	0.53
Splice Acceptor	34	0.51
Other Consequences	63	0.61

---

Known Limitations

• Trained primarily on ClinVar-labeled variants
• Limited indel generalization
• 401 bp receptive field (short-range context)
• Not validated for clinical decision-making
• Research-use only

---

Intended Use

This model is intended as:

• Research tool
• Variant prioritization support
• Experimental splice-aware classifier

Not intended for direct clinical decision-making.

---

Future Directions

• Expand receptive field (>2kb)
• Dilated convolutions
• Transformer-based architecture
• Multi-task pathogenicity + splice scoring
• Larger independent external validation

---

License

Research use only.

---

Author

Nilesh Hanotia