chr10-43106382-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_020975.6(RET):c.874G>A(p.Val292Met) variant causes a missense change. The variant allele was found at a frequency of 0.000227 in 1,610,770 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts 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
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.874G>A | p.Val292Met | missense_variant | Exon 5 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000361 AC: 55AN: 152202Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000625 AC: 154AN: 246360Hom.: 0 AF XY: 0.000612 AC XY: 82AN XY: 133944
GnomAD4 exome AF: 0.000212 AC: 309AN: 1458450Hom.: 4 Cov.: 32 AF XY: 0.000218 AC XY: 158AN XY: 725624
GnomAD4 genome AF: 0.000368 AC: 56AN: 152320Hom.: 1 Cov.: 33 AF XY: 0.000376 AC XY: 28AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:2
- -
This variant is denoted RET c.874G>A at the cDNA level, p.Val292Met (V292M) at the protein level, andresults in the change of a Valine to a Methionine (GTG>ATG). This variant was observed in at least one individual withpheochromocytoma and medullary thyroid cancer and four individuals with Hirschsprung disease (Castellone 2010, So2011, Ngo 2012). This variant has also been identified in 1/62 healthy East Asian individuals undergoing wholegenome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus theunaffected status of this individual may not be significant. RET Val292Met was observed at an allele frequency of0.624% (52/8336) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project,The 1000 Genomes Consortium 2015, Lek 2016).Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. RETVal292Met occurs at a position that is conserved across species and is located in the extracellular topological domainand cadherin domain (Garcia-Barcelo 2004). In silico analyses are inconsistent regarding the effect this variant mayhave on protein structure and function. Based on currently available evidence, it is unclear whether RET Val292Met isa pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
- -
- -
- -
- -
not specified Benign:2Other:1
The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. This variant has been seen where an alternate explanation for disease was also identified (PMID: 21655256; 32989896). This variant does not segregate with disease in at least one family (PMID: 32989896). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 20039896). -
- -
- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This alteration is classified as 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. -
- -
Multiple endocrine neoplasia type 2B Uncertain:1
- -
Pheochromocytoma Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Hirschsprung disease, susceptibility to, 1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Renal hypodysplasia/aplasia 1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Multiple endocrine neoplasia, type 2 Benign:1
- -
Multiple endocrine neoplasia Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Hereditary cancer Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at