rs878855065
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_020975.6(RET):c.57_65dup(p.Pro20_Leu22dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 35)
Exomes 𝑓: 0.0000022 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
RET
NM_020975.6 inframe_insertion
NM_020975.6 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.952
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.57_65dup | p.Pro20_Leu22dup | inframe_insertion | 1/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.57_65dup | p.Pro20_Leu22dup | inframe_insertion | 1/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 35
GnomAD3 genomes
?
Cov.:
35
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000221 AC: 3AN: 1359934Hom.: 0 Cov.: 30 AF XY: 0.00000149 AC XY: 1AN XY: 670820
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
3
AN:
1359934
Hom.:
Cov.:
30
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AC XY:
1
AN XY:
670820
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 35
GnomAD4 genome
?
Cov.:
35
Bravo
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 09, 2022 | This variant, c.57_65dup, results in the insertion of 3 amino acid(s) of the RET protein (p.Pro20_Leu22dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 241364). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2023 | The c.57_65dupGCCGCTGCT variant (also known as p.P20_L22dup), located in coding exon 1 of the RET gene, results from an in-frame duplication of GCCGCTGCT at nucleotide positions 57 to 65. This results in the duplication of 3 extra residues (PLL) between codons 20 and 22. This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at