Tag: Variant Annotation

Performance of Variant Annotators in Clinical Use

[PMID: 29179779] [Genome Biology]

Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines

“compared performance of 25 algorithms” on “14,819 benign or pathogenic missense variants from the ClinVar”



[PMID: 28851873] [Nature Communications]

Using ALoFT to determine the impact of putative loss-of-function variants in protein-coding genes

“Here, we present ALoFT (annotation of loss-of-function transcripts), a method to annotate and predict the disease-causing potential of loss-of-function variants. Using data from Mendelian disease-gene discovery projects, we show that ALoFT can distinguish between loss-of-function variants that are deleterious as heterozygotes and those causing disease only in the homozygous state. Investigation of variants discovered in healthy populations suggests that each individual carries at least two heterozygous premature stop alleles that could potentially lead to disease if present as homozygotes. ” Work from Daniel MacArthur & Mark Gerstein.


[PMID:28416821] [Nature Genetics]

Pathogenic variants that alter protein code often disrupt splicing

“We discovered that the alleles causing splicing defects cluster in disease-associated genes (for example, haploinsufficient genes). We analyzed 4,964 published disease-causing exonic mutations using a massively parallel splicing assay (MaPSy), which showed an 81% concordance rate with splicing in patient tissue. Approximately 10% of exonic mutations altered splicing, mostly by disrupting multiple stages of spliceosome assembly.”


[PMID:28502612] [American Journal of Human Genetics]

MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome

“MARRVEL (model organism aggregated resources for rare variant exploration) is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER.”