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Table 4 Examples of studies that effectively used prediction tools to study disease-causing synonymous variants

From: In silico methods for predicting functional synonymous variants

Disease association

Variant

Prediction tool

Description

Ref

Crohn’s disease

IRGM (c.313C > T)

SnipMir, RegRNA, and Patrocles (miRNA)

Synonymous variant predicted to delete a miRNA binding site, leading to increased risk for Crohn’s disease (validated to be the causal mechanism through experiments assessing IRGM regulation)

[175]

Cystic fibrosis

ΔF508 CFTR (c.1520_1522delTCT)

mFold (mRNA structure)

Synonymous site within the ΔF508 CFTR predicted to alter mRNA structure and stability and found to responsible for altered expression of the mutant protein

[18, 176]

Hemophilia B

FIX [Factor IX] (c.459G > A)

mFold, Kinefold, NUPACK (mRNA structure), RSCU, CAI (codon usage indices)

mRNA structure prediction tools indicated a moderate reduction in mRNA stability, which coincided with diminished FIX expression through decreased translational speed

[77]

Hereditary cardiac arrhythmia

hERG (codon-modified)

RNAfold (mRNA structure)

Codon modified hERG was predicted to have increased mRNA stability, resulting in altered translation of the ion channel

[19]

Pain sensitivity

COMT (3 haplotypes with synonymous variations [c.198A > G, c.186C > T, c.408C > G])

mFold (mRNA structure)

COMT haplotype with predicted highest mRNA stability correlated with the lowest activity and expression levels. Other haplotypes with different thermodynamic stabilities elicited different pain sensitivities

[147, 177]

Phenylketonuria

PAH (c.30C > G)

ESE Finder 3.0 (splicing)

An exonic splicing silencer was identified through splicing predictions and validated experimentally to be the main mechanism underlying the PKA-causing variant

[178]

Tuberculosis

mabA (c.609G > A)

GENETYX-MAC (promoter prediction)

Synonymous variant predicted to cause the formation of an alternative promoter site, next to the mutation position, which was validated and found to increase transcription of inhA, leading to increased isoniazid resistance

[155, 179]