10-43114547-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_020975.6(RET):c.1947G>A(p.Ser649=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S649S) has been classified as Likely benign.
Frequency
Consequence
NM_020975.6 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1947G>A | p.Ser649= | synonymous_variant | 11/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1947G>A | p.Ser649= | synonymous_variant | 11/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458686Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725790
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hirschsprung disease, susceptibility to, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Mar 10, 2021 | ACMG codes:PS4, PS3, PM2, PP5 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Feb 01, 2022 | - - |
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Multiple endocrine neoplasia, type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change affects codon 649 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RET protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Hirschsprung disease (PMID: 10618407, 21712996). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24929). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2023 | In silico analysis suggests this variant may impact gene splicing. Published RT-PCR studies demonstrate this variant results in an in-frame loss of 23 residues expressed as a hypomorphic allele (Bolk et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies describe c.1947G>A as a hypomorphic allele, and state that carriers may express an intermediate level of RET (Bolk et al.,2000); This variant is associated with the following publications: (PMID: 16448984, 10090908, 11955539, 21712996, 8896569, 10618407) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2022 | The c.1947G>A variant (also known as p.S649S), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide position 1947. This nucleotide substitution does not change the serine at codon 649. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. This alteration has been reported in multiple families affected with Hirschprung disease in the literature (Salomon R et al. Nat Genet, 1996 Nov;14:345-7; Auricchio A et al. Am J Hum Genet, 1999 Apr;64:1216-21; Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). Bolk et al. performed RT-PCR analysis on RNA from a lymphoblastoid line demonstrating that the alteration creates a novel splice acceptor site within RET and partial novel splice site usage results in the deletion of first 23 amino acids of exon 11. Authors concluded that based on partial usage of the novel splice acceptor site, the S649S mutation is a hypomorphic allele (Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). Based on the supporting evidence, this alteration is likely pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unknown. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at