Has anyone here used ALoFT with GRCh38 ?

[Joseph White]

Hi Everyone,

We are looking at 'loss of function' variants in the human genome. I am using a program called 'ALoFT' to identify LoF variants. Problem is that my data has GRCh38 chromosome and position.

Has anyone here used ALoFT with GRCh38 data files? (These are the resource files that ALoFT uses to make calls.) The program is downloaded with 'data' for hg19, but not hg38/grch38. I am looking for the latter. (Although there are scores for hg38 on the web site, the files are not quite the same format.)

Joe White

[ashishbansal]

ALoFT provides extensive annotation for SNPs that introduce a premature stop codon, SNPs affecting splice sites, and indels that lead to frameshift. Initial sequence-based annotation of coding variants is performed by the Variant Annotation Tool56*(VAT). The output of VAT is augmented with various features specific to pLoF variants. The input files can be in VCF format or a tab-delimited 5-column file that includes chromosome, variant position, variant ID, reference allele, and alternate allele. LoF variants annotated with various features are output as three separate files: a VCF-formatted file containing summarized annotations, a Tab-delimited file containing extensive annotations for premature stop variants and indels leading to frameshift, a tab-delimited file containing annotations for variants that affect the canonical splice sites

[ashishbansal]

I have used ALoFT. Variants predicted to result in the loss of function of human genes have attracted interest because of their clinical impact and surprising prevalence in healthy individuals. 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. When applied to de novo putative loss-of-function variants in autism-affected families, ALoFT distinguishes between deleterious variants in patients and benign variants in unaffected siblings. Finally, analysis of somatic variants in >6500 cancer exomes shows that putative loss-of-function variants predicted to be deleterious by ALoFT are enriched in known driver genes.