ClinGen Dosage Sensitivity Curation Page

SF3B4

  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22541558 In a cohort of 35 patients diagnosed with Nager syndrome, Bernier et al. (2012) found that 20 (57%) had mutations in SF3B4. A total of 18 different mutations were identified, and these included 14 frameshift, two nonsense, one splicing, and one missense mutation thought to preclude the initiation codon. In the 8 patients for whom parental DNA was available, 4 mutations were shown to be de novo and 4 of familial inheritance. Every family member that carried a mutation was considered affected suggesting complete penetrance.
23568615 Czeschik et al. (2013) performed exome sequencing in two patients, and Sanger sequencing of SF3B4 in 12 patients with the clinical diagnosis of Nager syndrome. Heterozygous mutations of SF3B4 were identified in 7 out of the 12 patients (63.6%). In all patients for whom parental DNA was available (n=4), the mutations were shown to be de novo. Of the 7 mutations: 3 were frameshift, 4 were nonsense of which one was predicted to affect the start codon and preclude protein synthesis from the affected allele. None of the patients carried a splice or a missense mutation.
24003905 Petit et al. (2013) identified SF3B4 mutations in 13/18 patients with Nager syndrome using Sanger sequencing. 9 different mutations were found, all of which were predicted to result in loss-of-function; these included 5 frameshift, 3 nonsense, 3 splicing, and two mutations predicted to preclude the initiation codon. In the 8 patients for whom parental DNA was available, 5 mutations were shown to be de novo and 3 of familial inheritance. Every family member that carried a mutation was diagnosed with Nager syndrome suggesting complete penetrance.

Haploinsufficiency phenotype comments:

The missense mutation, predicted to abolish the initiation codon, has now been identified in 4 unrelated families; the nonsense mutations c452C>A and c1006C>T in two unrelated families; and the frameshift mutations c1060dupC and c1006C>T in two unrelated families [Bernier et al., Czeschik et al. (PMID 23568615), and Petit et al. (PMID 24003905)]. No genotype-phenotype correlation has been found nor has compound heterozygosity. Given multiple independent reports of a large number of unrelated patients with Nager syndrome and mutations predicted to result in the loss-of-function of SF3B4, the ISCA haploinsufficiency score for this gene is 3. However, please note that thus far, only sequence-level mutations have been identified in association with Nager syndrome and reports of SF3B4 deletion have not yet emerged.

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