chr14-95094145-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3PM2_SupportingPM1_Supporting
This summary comes from the ClinGen Evidence Repository: NM_177438.2(DICER1):c.5107C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1703 (p.Arg1703Cys). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1_Supporting; PMID:31342592). The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PM1_Supporting, PP3 (Bayesian Points: 3; VCEP specifications version 1; 02/11/2022)). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10583187/MONDO:0017288/024
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.5107C>T | p.Arg1703Cys | missense_variant | 24/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.5107C>T | p.Arg1703Cys | missense_variant | 24/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461876Hom.: 1 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727240
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2022 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DICER1 protein function. ClinVar contains an entry for this variant (Variation ID: 242130). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1703 of the DICER1 protein (p.Arg1703Cys). - |
Uncertain significance, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | May 18, 2022 | NM_177438.2(DICER1):c.5107C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1703 (p.Arg1703Cys). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PM1_Supporting, PP3 (Bayesian Points: 3; VCEP specifications version 1; 02/11/2022)). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 14, 2022 | The p.R1703C variant (also known as c.5107C>T), located in coding exon 23 of the DICER1 gene, results from a C to T substitution at nucleotide position 5107. The arginine at codon 1703 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at