rs1416677590
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PM4_Supporting
The NM_020975.6(RET):βc.1934_1936delβ(p.Ser645del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000123 in 1,457,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. F644F) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.000012 ( 0 hom. )
Consequence
RET
NM_020975.6 inframe_deletion
NM_020975.6 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.98
Genes affected
RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 13 uncertain in NM_020975.6
PM4
Nonframeshift variant in NON repetitive region in NM_020975.6. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1934_1936del | p.Ser645del | inframe_deletion | 11/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1934_1936del | p.Ser645del | inframe_deletion | 11/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249244Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134920
GnomAD3 exomes
AF:
AC:
2
AN:
249244
Hom.:
AF XY:
AC XY:
2
AN XY:
134920
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1457952Hom.: 0 AF XY: 0.00000965 AC XY: 7AN XY: 725430
GnomAD4 exome
AF:
AC:
18
AN:
1457952
Hom.:
AF XY:
AC XY:
7
AN XY:
725430
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 13, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2024 | The c.1934_1936delCCT variant (also known as p.S645del) is located in coding exon 11 of the RET gene. This variant results from an in-frame CCT deletion at nucleotide positions 1934 to 1936. This results in the in-frame deletion of a serine at codon 645. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a multiple endocrine neoplasia type 2 (MEN2) disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, the association of this alteration with Hirschprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. - |
Multiple endocrine neoplasia type 2B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 02, 2019 | - - |
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This variant, c.1934_1936del, results in the deletion of 1 amino acid(s) of the RET protein (p.Ser645del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 543756). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Congenital anomaly of kidney and urinary tract Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | May 31, 2018 | This patient is heterozygous for a variant, c.1934_1936del (p.Ser645del), in the RET gene. This 3 base deletion removes a highly conserved (up to 11 species) serine residue at position 645. To our knowledge, c.1934_1936del (p.Ser645del) has not been previously reported in the literature to be associated with disease and it has not been reported in any allele frequency databases. This variant is considered to be a variant of uncertain significance (VOUS) according to the ACMG guidelines. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at