rs767654905
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_020975.6(RET):c.686T>C(p.Leu229Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,597,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L229L) has been classified as Likely benign.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.686T>C | p.Leu229Pro | missense_variant | 4/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.686T>C | p.Leu229Pro | missense_variant | 4/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000446 AC: 1AN: 224136Hom.: 0 AF XY: 0.00000814 AC XY: 1AN XY: 122882
GnomAD4 exome AF: 0.00000277 AC: 4AN: 1444952Hom.: 0 Cov.: 36 AF XY: 0.00000278 AC XY: 2AN XY: 718706
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 01, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 229 of the RET protein (p.Leu229Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 477382). This variant has not been reported in the literature in individuals affected with RET-related conditions. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 18, 2023 | The p.L229P variant (also known as c.686T>C), located in coding exon 4 of the RET gene, results from a T to C substitution at nucleotide position 686. The leucine at codon 229 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at