14-95091265-T-C
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_177438.3(DICER1):c.5465A>G(p.Asp1822Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1822V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.5465A>G | p.Asp1822Gly | missense_variant | 25/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.5465A>G | p.Asp1822Gly | missense_variant | 25/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | Nov 03, 2022 | The NM_177438.2:c.5465A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1822 (p.Asp1822Gly). This variant received a total of 2 phenotype points across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PS4_Moderate; Ambry). The variant has been reported to segregate with Sertoli Leydig cell tumors, PPB, and lung cysts in 4 meioses from 2 families (PP1; Ambry). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). The computational predictor REVEL gives a score of 0.956, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functional as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Moderate, PP1, PP3, PM1_Supporting, PM2_Supporting. (Bayesian Points: 6; VCEP specifications version 1.1.0; 10/25/2022) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1822 of the DICER1 protein (p.Asp1822Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of DICER1-related conditions (external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 429125). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Asp1822 amino acid residue in DICER1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21266384, 26925222). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2023 | The p.D1822G variant (also known as c.5465A>G), located in coding exon 24 of the DICER1 gene, results from an A to G substitution at nucleotide position 5465. The aspartic acid at codon 1822 is replaced by glycine, an amino acid with similar properties. This alteration has been observed in individuals with a personal and family history that is consistent with DICER1-related disease (Ambry internal data). This alteration has also been observed to co-segregate with DICER1-related disease with several families (Ambry internal data). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical function (de Kock L et al. Hum Mutat, 2019 Nov;40:1939-1953). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at