A review study: Computational techniques for expecting the impact of non-synonymous single nucleotide variants in human diseases

Hassan, Marwa; Shaalan, A. A.; Dessouky, Moawad I.; Abdelnaiem, Abdelaziz Elsaid; ElHefnawi, Mahmoud

doi:10.1016/j.gene.2018.09.028

Cited by 52 publications

(36 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Converging computational evidence from different bioinformatics tools is considered supporting evidence for either pathogenicity (PP3) or benignity (BP4). Apart from the programs specifically exploring splicing alteration, an abundance of tools has been developed to analyze missense variants, while others are suitable to predict the effect of coding and noncoding variants [ 111 ]. In many cases, tools rely on the evaluation of the evolutionary conservation, protein structure, or function (or a combination thereof).…”

Section: Applying the Acmg Standards And Guidelines For The Interpmentioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

View full text Add to dashboard Cite

The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS.

show abstract

Section: Applying the Acmg Standards And Guidelines For The Interpmentioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

View full text Add to dashboard Cite

show abstract

“…SIFT, PolyPhen2, CADD, SNAP2, FIRM (28)(29)(30)(31)(32)). Many of these tools incorporate long-range evolutionary information from cross-species conservation into the underlying model (33,34). We anticipate that the incorporation of short-term human baseline models such as HA 3 could be beneficial to these efforts.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary and Functional Lessons from Human-Specific Amino-Acid Substitution Matrices

Shauli

Brandes

Linial

2020

Preprint

View full text Add to dashboard Cite

The characterization of human genetic variation in coding regions is fundamental to our understanding of protein function, structure, and evolution. Amino-acid (AA) substitution matrices such as BLOSUM (BLOcks SUbstitution Matrix) and PAM (Point Accepted Mutations) encapsulate the stochastic nature of such proteomic variation and are used in studying protein families and evolutionary processes. However, these matrices were constructed from protein sequences spanning long evolutionary distances and are not designed to reflect polymorphism within species. To accurately represent proteomic variation within the human population, we constructed a set of human-centric substitution matrices derived from genetic variations by analyzing the frequencies of >4.8M single nucleotide variants (SNVs). These human-specific matrices expose short-term evolutionary trends at both codon and AA resolution and therefore present an evolutionary perspective that differs from that implicated in the traditional matrices. Specifically, our matrices consider the directionality of variants, and uncover a set of AA pairs that exhibit a strong tendency to substitute in a specific direction. We further demonstrate that the substitution rates of nucleotides only partially determine AA substitution rates. Finally, we investigate AA substitutions in posttranslational modification (PTM) and ion-binding sites. We confirm a strong propensity towards conservation of the identity of the AA that participates in such functions. The empirically-derived human-specific substitution matrices expose purifying selection over a range of residue-based protein properties. The new substitution matrices provide a robust baseline for the analysis of protein variations in health and disease. The underlying methodology is available as an openaccess to the biomedical community.

show abstract

“…It is used to assess the possible functional influence of nonsynonymous (single or multiple nonsynonymous) and in-frame indel (insertions and deletions) variations on a protein. It predicts the variation as deleterious or natural, if the functional impact score is less than or equal to − 2.5 (≤ − 2.5) it is estimated deleterious; score above − 2.5 (> − 2.5) is estimated neutral [77].…”

Section: Predicting the Most Deleterious Missense Nssnpsmentioning

confidence: 99%

“…This server determines whether a certain amino acid substitution is related to disease or neutral by protein sequence information, protein structure, conservation and solvent accessibility. The output is a probability index with a score of 0.0 to 1.0, when the score is higher than 0.5, the substituted amino acid is pathogenic [77,81].…”

Section: Yes [59]mentioning

confidence: 99%

Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences

et al. 2020

View full text Add to dashboard Cite

Background: The Human Leukocyte Antigen G (HLA-G) protein is an immune tolerogenic molecule with 7 isoforms. The change of expression level and some polymorphisms of the HLA-G gene are involved in various pathologies. Therefore, this study aimed to predict the most deleterious missense non-synonymous single nucleotide polymorphisms (nsSNPs) in HLA-G isoforms via in silico analyses and to examine structural and functional effects of the predicted nsSNPs on HLA-G isoforms. Results: Out of 301 reported SNPs in dbSNP, 35 missense SNPs in isoform 1, 35 missense SNPs in isoform 5, 8 missense SNPs in all membrane-bound HLA-G isoforms and 8 missense SNPs in all soluble HLA-G isoforms were predicted as deleterious by all eight servers (SIFT, PROVEAN, PolyPhen-2, I-Mutant 3.0, SNPs&GO, PhD-SNP, SNAP2, and MUpro). The Structural and functional effects of the predicted nsSNPs on HLA-G isoforms were determined by MutPred2 and HOPE servers, respectively. Consurf analyses showed that the majority of the predicted nsSNPs occur in conserved sites. I-TASSER and Chimera were used for modeling of the predicted nsSNPs. rs182801644 and rs771111444 were related to creating functional patterns in 5′UTR. 5 SNPs in 3′UTR of the HLA-G gene were predicted to affect the miRNA target sites. Kaplan-Meier analysis showed the HLA-G deregulation can serve as a prognostic marker for some cancers. Conclusions: The implementation of in silico SNP prioritization methods provides a great framework for the recognition of functional SNPs. The results obtained from the current study would be called laboratory investigations.

show abstract

A review study: Computational techniques for expecting the impact of non-synonymous single nucleotide variants in human diseases

Cited by 52 publications

References 61 publications

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Evolutionary and Functional Lessons from Human-Specific Amino-Acid Substitution Matrices

Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences

Contact Info

Product

Resources

About