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Table 1 Results of the in silico prediction analysis of pathogenicity of the novel GNAS variant

From: A complex pheotype in a girl with a novel heterozygous missense variant (p.Ile56Phe) of the GNAS gene

Germline allelic variant

Pathogenicity Prediction/Score

Conservation score

Varsome (Genome Interpretor)*

ACMG/AMP* criteria

DANN(a)

Mutation Taster(b)

FATHMM-MKL(c)

EIGEN(d)

GERP(e)

PhyloP100way(f)

PhastCons100way(g)

fitCons (GM12878/ H1-hESC/ HUVEC)(h)

Integrated fitCons(i)

bstatistic(l)

NM_0011077488: c.166A > T

p.I56F

Likely pathogenic

PM1#1 moderate PM2#2 moderate PP2#3 supporting PP3#4 supporting

0.99

Disease causing

Damaging

Pathogenic

5,63

8.95

1

0.67/0,68/0,72

0.65

986

  1. *The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) criteria: #1 Null variant (nonsense, frameshift, canonical ± 1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease—#2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium—#3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)—#4 Pathogenic computational verdict based on 13 pathogenic predictions vs no benign predictions; (a) pathogenicity scoring methodology based on deep neural networks; (b) the pathogenicity of a variant based on evolutionary conservation, splice-site, mRNA, protein and regulatory features; (c) predict the functional consequences of non-coding and coding single nucleotide variants (SNVs); (d) spectral approach to the functional annotation of genetic variants in coding and noncoding regions; (e) Genomic Evolutionary Rate Profiling, a conservation score calculated by quantifying substitution deficits across multiple alignments of orthologues using the genomes of 35 mammals; (f) Phylogenetic P-values, scores based on multiple alignments of 99 vertebrate genome sequences to the human genome; (g) identify evolutionarily conserved elements in a multiple alignment, given a phylogenetic tree, based on 100 vertebrate genomes (including human); (h) FITness CONSequences of functional annotation, identifies genomic regions under selective pressure by integrating epigenomic signals from three ENCODE cell lines (GM12878, H1-hESC and HUVEC) with selective pressure inferred using the INSIGHT ((Inference of Natural Selection from Interspersed Genomically coHerent elemenTs) method; (i) integrates functional assays (such as ChIP-Seq) with selective pressure inferred using the INSIGHT method.; (l) indicates the expected fraction of neutral diversity that is present at a site, based on human single nucleotide polymorphism (SNP) data
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Orphanet Journal of Rare Diseases

ISSN: 1750-1172