rs747901058
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_177438.3(DICER1):c.4616C>T(p.Thr1539Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,614,050 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1539K) has been classified as Uncertain significance.
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.4616C>T | p.Thr1539Met | missense_variant | 23/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.4616C>T | p.Thr1539Met | missense_variant | 23/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251460Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135904
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727246
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74320
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 22, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed with a truncating DICER1 variant (phase unknown) in four individuals from a single family, each with DICER1-related tumors (Kuhlen et al., 2015); This variant is associated with the following publications: (PMID: 29708584, 29762508, 28748527, 35384518, 26526666) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2022 | The p.T1539M variant (also known as c.4616C>T), located in coding exon 22 of the DICER1 gene, results from a C to T substitution at nucleotide position 4616. The threonine at codon 1539 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in four individuals from one family who were all affected with DICER1-related tumors; however, these individuals were also found to carry a truncating DICER1 mutation in addition to this alteration (Kuhlen M et al. Eur. J. Pediatr. 2016 Apr;175:593-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | curation | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 01, 2019 | ACMG criteria met: BP1, BP2, PB4 - |
DICER1-related tumor predisposition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at