ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000022.10) (NC_000022.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
25284784 This study (Dong et al, 2014) examined de novo insertions and deletions in 787 families included in the Simons Simplex Collection. A de novo frameshift variant, c.1352_1355del, p.(Phe451Leufs*14), in TNRC6B was detected and confirmed in a male proband.
25363768 This study (Iossifov et al, 2014) used exome sequencing to identify de novo variants in >2500 simplex ASD families from the Simons Simplex Collection. Two de novo variants were detected in two independent male probands (1 frameshift - same as Dong et al, and 1 nonsense, NM_015088.2:c.2479C>T, p.Gln827*) (Supplementary Table 2).
27479843 Lelieveld et al (2016) identified de novo variants from exomes of 2,104 intellectual disability trios (RUMC cohort). A confirmed de novo nonsense variant, NM_001162501.1:c.3343C>T, p.R1115* was detected in TNRC6B. Of note, this variant is observed in gnomAD (1 European [non-Finnish] allele out of 249190, frequency 4.01e-6) as of June 2019.

Haploinsufficiency phenotype comments:

Loss-of function de novo sequence variants in TNRC6B have been detected in probands with autism spectrum disorder and intellectual disability (at least 8 de novo independent variants). One larger deletion (66kb) intragenic to TNRC6B has also been detected in an individual with developmental delay [inheritance unknown, Decipher patient 346766]. Loss-of-function variants are also present in control individuals included in the gnomAD database, but at a frequency lower than expected for the gene (o/e=0.1). The gnomAD pLI for this gene is 1.0 and the DECIPHER HI index is 5.61%, suggesting this gene may be intolerant to loss-of-function variation. Additional references: PMID: 28191889 - In this study, Stessman et al (2017) sequenced 208 candidate genes from >11,730 cases with autism and developmental disabilities and >2,867 controls. A confirmed de novo frameshift variant, c.754dup, p.Glu252Glyfs*3, was detected in a proband from the AGRE cohort. Additional loss-of-function variants are included in Supplementary table 11 with inheritance unknown. PMID: 30564305 - In this study, Guo et al (2018) used targeted gene sequencing to investigate individuals included in the Autism Clinical and Genetic Resources in China (Phase 2). Two de novo loss-of-function variants were detected in TNRC6B. The first was a nonsense variant, c.1879C>T, p.Q627* and the second was a deletion, c.4892del, p.Trp1625Glyfs*40. PMID: 30504930 - In this study, Guo et al (2018) used whole genome sequencing to investigate 108 simplex and multiplex autism spectrum disorder families from the SAGE cohort. A splice site mutation (NM_001024843.1:c.46-2A>G), was detected in a proband and his father. Phenotype information for the father was not presented. This variant is also present in the gnomAD population dataset (0.0046% MAF). PMID: 29463886 - In this study, Eising et al (2018) complete whole genome sequencing of 19 childhood apraxia of speech (CAS) trios and detected a de novo TNRC6B variant (c.2040G>A, p.W680*) in one proband with CAS and autism spectrum disorder (Case 15).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No whole gene duplications reported at this time