Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_020975.6(RET):c.-6C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 35)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
RET NM_020975.6 5_prime_UTR_premature_start_codon_gain
Scores
2
Clinical Significance
Uncertain significance criteria provided, single submitter U:1
RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Describes a nucleotide substitution 6 base pairs upstream of the ATG translational start site of the RET gene, occurring in the Kozak sequence, the conserved nucleotides just upstream of the ATG start codon, which play a major role in the initiation of translation; Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016) -