rs536298339
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_020975.6(RET):āc.1150C>Gā(p.Pro384Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. P384R) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1150C>G | p.Pro384Ala | missense_variant | 6/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1150C>G | p.Pro384Ala | missense_variant | 6/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251040Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135808
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461644Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727134
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152302Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74462
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia type 2B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 14, 2016 | - - |
Multiple endocrine neoplasia type 2A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 14, 2016 | - - |
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 384 of the RET protein (p.Pro384Ala). This variant is present in population databases (rs536298339, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216713). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at