rs752830820
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_020975.6(RET):c.1574G>A(p.Arg525Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,594,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1574G>A | p.Arg525Gln | missense_variant | 8/20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1574G>A | p.Arg525Gln | missense_variant | 8/20 | 5 | NM_020975.6 | ENSP00000347942.3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000235 AC: 5AN: 212994Hom.: 0 AF XY: 0.0000348 AC XY: 4AN XY: 114900
GnomAD4 exome AF: 0.0000104 AC: 15AN: 1442480Hom.: 0 Cov.: 32 AF XY: 0.0000168 AC XY: 12AN XY: 715510
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74390
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 07, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 525 of the RET protein (p.Arg525Gln). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 477321). This variant has not been reported in the literature in individuals affected with RET-related conditions. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 08, 2023 | - - |
Multiple endocrine neoplasia type 2A Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 08, 2024 | This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at