10-43077265-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_020975.6(RET):c.7A>G(p.Lys3Glu) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.7A>G | p.Lys3Glu | missense_variant | Exon 1 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 35
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1352642Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 667142
GnomAD4 genome Cov.: 35
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:2
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This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 3 of the RET protein (p.Lys3Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RET-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 584566). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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:2
The p.K3E variant (also known as c.7A>G), located in coding exon 1 of the RET gene, results from an A to G substitution at nucleotide position 7. The lysine at codon 3 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at