rs370736139
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5BP4_ModerateBP6
The NM_020975.6(RET):c.539G>A(p.Arg180Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180G) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.539G>A | p.Arg180Gln | missense_variant | 3/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.539G>A | p.Arg180Gln | missense_variant | 3/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251346Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135870
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 727236
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334
ClinVar
Submissions by phenotype
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 18, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Multiple endocrine neoplasia, type 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with glutamine at codon 180 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MEN2 or medullary thyroid carcinoma. This variant has been reported in an individual affected with Hirschsprung disease (PMID: 10790203). This variant has been identified in 37/282728 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Aganglionic megacolon Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 18, 2015 | - - |
Familial medullary thyroid carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 10, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2023 | The RET c.539G>A; p.Arg180Gln variant (rs370736139) is reported in the literature in an individual affected with Hirschsprung disease (Hofstra 2000). This variant is also reported in ClinVar (Variation ID: 161360). This variant is found in the Latino population with an allele frequency of 0.08% (27/35,432 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.223). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Hofstra RM et al. RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Hum Mutat. 2000;15(5):418-29. PMID: 10790203. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2020 | 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