PON-PS

PON-PS predicts the phenotypic severity due to amino acid substitutions. The method is trained by using severe and mild/moderate (called as non-severe) disease-causing variations and uses evolutionary conservation, properties of amino acids and sequence environment for prediction. PON-PS uses the PON-P2 predictor to filter out benign variations. The severity of the remaining variants are predicting by an ensemble of 100 random forest predictors.

The training and test datasets used in PON-PS are available in VariBench database.

The manuscript describing the method has been published in Human Mutation here.

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Submitting queries

PON-PS requires users to submit fasta-format amino acid sequence(s) and variation(s) in the corresponding sequence(s). Each sequence should have a header line starting with greater than sign (>) followed by description. The first 15 characters of the description for each sequence should be unique. The sequence in upper-case characters follows the header line. No characters except the universal 20 amino acid codes are accepted in the sequence(s). The variation(s) corresponding to a sequence should contain the same header line as the sequence. Variation(s) follow the header line and only one variation is allowed per line. The sequence(s) and variation(s) can be pasted in the correponding text-boxes or separate files containing sequence(s) and variation(s) can be submitted.
Example sequences:
>ADA_HUMAN
MAQTPAFDKPKVELHVHLDGSIKPETILYYGRRRGIALPANTAEGLLNVIGMDKPLTLPD
FLAKFDYYMPAIAGCREAIKRIAYEFVEMKAKEGVVYVEVRYSPHLLANSKVEPIPWNQA
EGDLTPDEVVALVGQGLQEGERDFGVKARSILCCMRHQPNWSPKVVELCKKYQQQTVVAI
DLAGDETIPGSSLLPGHVQAYQEAVKSGIHRTVHAGEVGSAEVVKEAVDILKTERLGHGY
HTLEDQALYNRLRQENMHFEICPWSSYLTGAWKPDTEHAVIRLKNDQANYSLNTDDPLIF
KSTLDTDYQMTKRDMGFTEEEFKRLNINAAKSSFLPEDEKRELLDLLYKAYGMPPSASAG
QNL
>Retinal pigment
MSIQVEHPAGGYKKLFETVEELSSPLTAHVTGRIPLWLTGSLLRCGPGLFEVGSEPFYHL
FDGQALLHKFDFKEGHVTYHRRFIRTDAYVRAMTEKRIVITEFGTCAFPDPCKNIFSRFF
SYFRGVEVTDNALVNVYPVGEDYYACTETNFITKINPETLETIKQVDLCNYVSVNGATAH
PHIENDGTVYNIGNCFGKNFSIAYNIVKIPPLQADKEDPISKSEIVVQFPCSDRFKPSYV
HSFGLTPNYIVFVETPVKINLFKFLSSWSLWGANYMDCFESNETMGVWLHIADKKRKKYL
NNKYRTSPFNLFHHINTYEDNGFLIVDLCCWKGFEFVYNYLYLANLRENWEEVKKNARKA
PQPEVRRYVLPLNIDKADTGKNLVTLPNTTATAILCSDETIWLEPEVLFSGPRQAFEFPQ
INYQKYCGKPYTYAYGLGLNHFVPDRLCKLNVKTKETWVWQEPDSYPSEPIFVSHPDALE
EDDGVVLSVVVSPGAGQKPAYLLILNAKDLSEVARAEVEINIPVTFHGLFKKS

Variation examples:
>ADA_HUMAN
R101H #reference amino acid,position in the sequence(1 based),variant amino acid
R101L
S291L
>Retinal pigment
G75R
R97P

Email:
Users are required to submit a valid email address where the results will be sent when they are ready.

PON-PS output

PON-PS sends the prediction results as attachments to the provided email id. The result file contains following columns.
1) Protein_description: First 15 characters of the protein sequence description
2) Amino_acid_substitution: Amino acid substitution
3) PON-P2_score: PON-P2 predicted probability of pathogenicity
4) PON-P2_prediction: Prediction of pathogenicity for amino acid substitution by PON-P2 (one of Neutral, Unknown or Pathogenic)
5) PON-PS_score: Predicted probability of being severe (only for variation predicted pathogenic or unknown by PON-P2). It ranges from 0 (non-severe) to 1 (severe).
6) PON-PS_prediction: Predicted severity class of variation (only for variation predicted pathogenic or unknown by PON-P2).

How to cite?
Niroula A and Vihinen M (2017) Predicting Severity of Disease-Causing Variants. Hum Mutat 38(4):357-364.

If you have any queries, please feel free to contact us.