The mutational constraint spectrum quantified from variation in 141,456 humans

Abstract

Supplemental Figure 1 Method: All MS runs were compared and clustered using standard artMS ( https://github.com/biodavidjm/artMS ) procedures on observed feature intensities computed by MaxQuant. Supplemental Figure 1 shows all Pearson's pairwise correlations between MS runs, and are clustered according to similar correlation patterns. Supplemental Figure 2 Method: See main text. Supplemental Figure 3 Method: PFAM domain enrichment analysis. The enrichment of individual PFAM domains (or PFAM clans) 1 was calculated with a hypergeometric test where success is defined as number of domains, and the number of trials is the number of individual preys pulled-down with each viral bait. The population values were the numbers of individual PFAM domains and clans in the human proteome.To make sure that the p-values that signify enrichment were meaningful, we only considered PFAM domains that have been pulled-down at least three times with any SARS-CoV-2 protein, and which occur in the human proteome at least five times. In SI Figure 3 we show PFAM domains/clans with the lowest p-value for a given viral bait protein.

Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

“…One of the most difficult challenges currently facing human genetics is determining whether or not a given missense variant in an individual with a disease is pathogenic and assigning a potential etiological molecular diagnosis. Extensive allelic heterogeneity and genotype/phenotype correlations are more readily interpretable for loss‐of‐function truncating variants, now that some population datasets of normal control individuals are large enough to enable case‐control calculations for this class of variants (DeBoever et al, ; Karczewski, Francioli, Tiao, & Cummings, ; Lek et al, ; Van Hout et al, ). A population‐scale study ranked TAF1 53rd among the top 1,003 constrained human genes (Samocha et al, ), indicating a critical role for this protein in normal cellular functioning, and TAF1 is highly conserved, with a calculated probability of loss‐of‐function intolerance (pLI) of 1.0 (genes with pLI ≥ .9 are considered extremely loss of function intolerant) (Lek et al, ).…”

A toolkit for genetics providers in follow‐up of patients with non‐diagnostic exome sequencing

“…The American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG‐AMP) Guidelines for Sequence Variant Interpretation were published in order to support clinical laboratories in making more consistent interpretations (Richards et al, ). Large databases have become publicly available that help to assess variants in apparently healthy populations (Exome Aggregation Consortium in October 2014 (Lek et al, ); and Genome Aggregation Database in February 2017 Karczewski et al, ). We used MutationTaster (Schwarz, Cooper, Schuelke, & Seelow, ) to assess pathogenicity of the KCTD7 p.Val152Val variant, which incorporates splicing predictions from NNSplice (Reese, Eeckman, Kulp, & Haussler, ).…”

The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype

“…The c.139G>A variant in RHOA , which we detected in all four individuals, is not observed in any current database of human genetic variations including the ExAC (http://exac.broadinstitute.org) and gnomAD (https://gnomad.broadinstitute.org) database (access date 27/11/2019; Karczewski et al, ; Lek et al, ). It is predicted to lead to the substitution of a phylogenetically highly conserved glutamate at the amino acid position 47 of RHOA by lysine (p.Glu47Lys; Figure i–k).…”