The mutation significance cutoff: gene-level thresholds for variant predictions

Itan, Yuval; Shang, Lei; Boisson, Bertrand; Ciancanelli, Michael J.; Markle, Janet; Martı́nez-Barricarte, Rubén; Scott, Eric; Shah, I; Stenson, Peter D.; Gleeson, Joseph G.; Cooper, David Neil; Quintana-Murci, Lluı́s; Zhang, Shen-Ying; Abel, Laurent; Casanova, Jean‐Laurent

doi:10.1038/nmeth.3739

Cited by 259 publications

(258 citation statements)

References 9 publications

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“…The p.D387N missense mutation affected a residue conserved throughout evolution. As expected, combined annotation dependent depletion (CADD) scores predicted all mutations to be deleterious and were well above the mutation significance cutoff score for IL17RA (Table 1) (64,65). These data strongly suggested that the 21 patients suffered from AR IL-17RA deficiency.…”

Section: Resultssupporting

confidence: 67%

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Lévy

Okada

Béziat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensalCandidaspecies. The first genetic etiology of isolated CMC—autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency—was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity toCandidaandStaphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

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Section: Resultssupporting

confidence: 67%

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Lévy

Okada

Béziat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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146

127

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“…Moreover, these mutations also have the four highest damage prediction scores (CADD, combined annotation dependent depletion) of all the variants found to be homozygous (Fig. 1D) (33, 34). Together, these findings strongly suggest that the homozygous ZNF341 mutations identified in these patients are both deleterious and disease-causing.…”

Section: Resultsmentioning

confidence: 86%

“…The dotted line corresponds to the mutation significance cutoff (MSC). The CADD scores of 34, 35, 36 and 40 for the Q195X, K355fs/K362fs, Y542X/Y549X and R302X mutations, respectively, are well above the MSC of 3.31 for ZNF341 (34) . The ZNF341 gene has intermediate gene damage index (GDI) and neutrality index (NI) scores, of 3.72 and 0.30, respectively, suggesting that ZNF341 is not under strong purifying selection, consistent with the segregation of ZNF341 deficiency as an AR disorder.…”

Section: Figmentioning

confidence: 82%

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

et al. 2018

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Heterozygosity for human STAT3 dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-IgE syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341. ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including, most notably the STAT3 promoter. The patients’ cells have low basal levels of STAT3 mRNA and protein. The auto-induction of STAT3 production, activation, and function by STAT3-activating cytokines is particularly strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack Th17 cells, have an excess of Th2 cells, and low memory B cells, due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341-dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent auto-induction and sustained activity of STAT3.

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“…P1 and P2, two Belgian boys, were aged 3 and 5 years, respectively when they were seen in hospital due to VZV encephalitis (P1) and cerebellitis (P2). P3 and P4, one boy and one girl, born to French and German parents, respectively, were aged 5 and 11 years when they developed VZV pneumonitis (P3) and encephalitis (P4 the predicted Mutation Significance Cutoffs (MSC) of 95% confidence (Supplemental Figure 3) (32,33). The genes themselves are highly conserved and subject to purifying selection, with low gene damage index and purification coefficient (34).…”

Section: Identification Of Heterozygous Mutations In Polr3a and Polr3mentioning

confidence: 99%

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Ogunjimi¹,

Zhang²,

Sørensen³

et al. 2017

Journal of Clinical Investigation

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The mutation significance cutoff: gene-level thresholds for variant predictions

Cited by 259 publications

References 9 publications

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

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