Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_177438.3(DICER1):c.5428G>T (p.Asp1810Tyr)

CA390864677

933084 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: fdd778e8-91ef-441d-a892-61afa8dca6f3
Approved on: 2025-01-07
Published on: 2025-01-27

HGVS expressions

NM_177438.3:c.5428G>T
NM_177438.3(DICER1):c.5428G>T (p.Asp1810Tyr)
NC_000014.9:g.95091302C>A
CM000676.2:g.95091302C>A
NC_000014.8:g.95557639C>A
CM000676.1:g.95557639C>A
NC_000014.7:g.94627392C>A
NG_016311.1:g.71121G>T
ENST00000529720.2:c.5428G>T
ENST00000531162.7:c.5428G>T
ENST00000674628.2:c.5428G>T
ENST00000675540.2:c.*2078G>T
ENST00000696733.1:c.*50G>T
ENST00000696734.1:c.*83G>T
ENST00000696735.1:n.2415G>T
ENST00000696736.1:c.5428G>T
ENST00000696920.1:n.5691G>T
ENST00000696921.1:n.6534G>T
ENST00000696922.1:n.8359G>T
ENST00000696923.1:c.*83G>T
ENST00000696924.1:c.*50G>T
ENST00000696925.1:n.8359G>T
ENST00000343455.8:c.5428G>T
ENST00000393063.6:c.5428G>T
ENST00000526495.6:c.5428G>T
ENST00000556045.6:c.*145G>T
ENST00000675540.1:c.3173G>T
ENST00000675995.1:c.*3744G>T
ENST00000343455.7:c.5428G>T
ENST00000393063.5:c.5428G>T
ENST00000526495.5:c.5428G>T
ENST00000527414.5:c.5428G>T
ENST00000527416.2:n.21G>T
ENST00000527554.2:n.121G>T
ENST00000541352.5:c.5365-193G>T
ENST00000556045.5:c.2122G>T
NM_001195573.1:c.5365-193G>T
NM_001271282.2:c.5428G>T
NM_001291628.1:c.5428G>T
NM_030621.4:c.5428G>T
NM_177438.2:c.5428G>T
NM_001271282.3:c.5428G>T
NM_001291628.2:c.5428G>T
NM_001395677.1:c.5428G>T
NM_001395678.1:c.5428G>T
NM_001395679.1:c.5428G>T
NM_001395680.1:c.5428G>T
NM_001395682.1:c.5428G>T
NM_001395683.1:c.5428G>T
NM_001395684.1:c.5428G>T
NM_001395685.1:c.5428G>T
NM_001395686.1:c.5146G>T
NM_001395687.1:c.5023G>T
NM_001395688.1:c.5023G>T
NM_001395689.1:c.5023G>T
NM_001395690.1:c.5023G>T
NM_001395691.1:c.4861G>T
NM_001395697.1:c.3745G>T
NR_172715.1:n.5846G>T
NR_172716.1:n.6030G>T
NR_172717.1:n.5940G>T
NR_172718.1:n.5863G>T
NR_172719.1:n.5696G>T
NR_172720.1:n.5899G>T
More

Pathogenic

Met criteria codes 6
PP3 PM1 PS4_Supporting PM2_Supporting PS3_Supporting PS2
Not Met criteria codes 12
BA1 PP4 PP1 PM3 PM5 BS2 BS4 BS3 BS1 BP2 BP4 PS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
The NM_177438.2:c.5428G>T variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by tyrosine at amino acid 1810 (p.Asp1810Tyr). This variant received a total of 1 phenotype point across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting, PMID: 26925222). This variant was identified as a de novo occurrence with constitutional mosaicism (PS2; PMID: 26925222). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assays showed that this variant fails to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting, PMID:26545620). The computational predictor REVEL gives a score of 0.923, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). This variant resides in the p.D1810 metal ion-binding residue located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1, PMID: 31342592). In summary, this variant meets the criteria to be classified as PATHOGENIC for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PS2, PM2_Supporting, PS3_Supporting, PP3, PM1 (Bayesian Points: 10; VCEP specifications version 1.3.0; 01/07/2025).
Met criteria codes
PP3
REVEL = 0.923 (>0.75); SpliceAI predicts DG 0.12 (2bps). MES does not predict exonic variant
PM1
Putative missense variants at residues affecting RNase Iib domain metal ion-binding
PS4_Supporting
1pt: Reported in 1 constitutional mosaic child with PPB type Ir, cystic nephroma, and two separate SLCTs (PMID 26925222). The following PMIDs were reviewed and this variant was described as a somatic finding and these PMIDs did not contribute evidence for classification: 35986592, 33567437, 33135284, 33595736, 34377011, 31900434, 31296931, 30260442, 30266945, 29474644, 29726952, 29881993, 28323992, 29037807, 26592504, 27459524, 24675358, 24909177, 22187960, 21205968.
PM2_Supporting
Absent in gnomad v4.1.0 (good coverage)
PS3_Supporting
1pt: In vitro cleavage assays showed a defect in 5p miRNA generation. In vitro exon cassette assay also suggests that c.5428G>T does create a cryptic splice site, which is predicted to be translated to a shorter protein, p.K1844fsX17 (abbreviated to ShEX25). In vitro cleavage assay showed that ShEX25 DICER1 protein did not produce 5p or 3p miRNAs. PMID 26545620
PS2
2pts: Confirmed de novo (constitutional mosaicism) in 1 proband with high-specificity phenotypes. (PMIDs: 26925222)
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
n/a
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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