rs80236571
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_020975.6(RET):c.989G>A(p.Arg330Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,426 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R330W) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.989G>A | p.Arg330Gln | missense_variant | 5/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.989G>A | p.Arg330Gln | missense_variant | 5/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461426Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727008
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 22, 2023 | The variant has been reported in patients affected with AD Hirschsprung disease. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect RET protein function (PMID: 8894691). This variant has been observed in individuals and families with Hirschsprung disase (PMID: 7633441, 8114939, 7581377). ClinVar contains an entry for this variant (Variation ID: 13926). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 330 of the RET protein (p.Arg330Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. - |
Hirschsprung disease, susceptibility to, 1 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jan 27, 1994 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at