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_030621.4(DICER1):c.5125G>A (p.Asp1709Asn)

CA390865395

690480 (ClinVar)

Gene: DICER1 (HGNC:23405)
Condition: dicer1 syndrome (MONDO:0017288)
Inheritance Mode: Autosomal dominant inheritance
UUID: d7bb7946-aea7-4885-9715-4a46a61fd29f
Approved on: 2022-05-17
Published on: 2022-07-08

HGVS expressions

NM_030621.4:c.5125G>A
NM_030621.4(DICER1):c.5125G>A (p.Asp1709Asn)
NC_000014.9:g.95094127C>T
CM000676.2:g.95094127C>T
NC_000014.8:g.95560464C>T
CM000676.1:g.95560464C>T
NC_000014.7:g.94630217C>T
NG_016311.1:g.68296G>A
ENST00000529720.2:c.5125G>A
ENST00000531162.7:c.5125G>A
ENST00000674628.2:c.5125G>A
ENST00000675540.2:c.*1775G>A
ENST00000696733.1:c.5125G>A
ENST00000696734.1:c.5125G>A
ENST00000696735.1:n.2112G>A
ENST00000696736.1:c.5125G>A
ENST00000696920.1:n.5388G>A
ENST00000696921.1:n.6231G>A
ENST00000696922.1:n.5534G>A
ENST00000696923.1:c.5125G>A
ENST00000696924.1:c.5125G>A
ENST00000696925.1:n.5534G>A
ENST00000343455.8:c.5125G>A
ENST00000393063.6:c.5125G>A
ENST00000526495.6:c.5125G>A
ENST00000556045.6:c.5125G>A
ENST00000675540.1:c.2870G>A
ENST00000675995.1:c.*3441G>A
ENST00000343455.7:c.5125G>A
ENST00000393063.5:c.5125G>A
ENST00000526495.5:c.5125G>A
ENST00000527414.5:c.5125G>A
ENST00000541352.5:c.5125G>A
ENST00000556045.5:c.1819G>A
NM_001195573.1:c.5125G>A
NM_001271282.2:c.5125G>A
NM_001291628.1:c.5125G>A
NM_177438.2:c.5125G>A
NM_001271282.3:c.5125G>A
NM_001291628.2:c.5125G>A
NM_177438.3:c.5125G>A
NM_001395677.1:c.5125G>A
NM_001395678.1:c.5125G>A
NM_001395679.1:c.5125G>A
NM_001395680.1:c.5125G>A
NM_001395682.1:c.5125G>A
NM_001395683.1:c.5125G>A
NM_001395684.1:c.5125G>A
NM_001395685.1:c.5125G>A
NM_001395686.1:c.4843G>A
NM_001395687.1:c.4720G>A
NM_001395688.1:c.4720G>A
NM_001395689.1:c.4720G>A
NM_001395690.1:c.4720G>A
NM_001395691.1:c.4558G>A
NM_001395697.1:c.3442G>A
NR_172715.1:n.5543G>A
NR_172716.1:n.5727G>A
NR_172717.1:n.5637G>A
NR_172718.1:n.5560G>A
NR_172719.1:n.5393G>A
NR_172720.1:n.5470G>A
More

Pathogenic

Met criteria codes 6
PP3 PS4_Moderate PM1 PM2_Supporting PS2_Very Strong PS3_Supporting
Not Met criteria codes 10
PP1 PP4 PM5 BA1 BS1 BS4 BS3 BP4 BP2 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

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.5125G>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1709 (p.Asp1709Asn). 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, PMIDs: 26925222, 26475046). In both probands, this variant was identified as a de novo occurrence with constitutional mosaicism (PS2_Very Strong; PMIDs: 26925222, 26475046). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). In vitro cleavage assays in HEK293 cells showed that this variant fails to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting, PMIDs: 22187960, 26545620). The computational predictor REVEL gives a score of 0.868, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). This variant resides in the p.D1709 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_Moderate, PS2_Very Strong, PM2_Supporting, PS3_Supporting, PP3, PM1. (Bayesian Points: 15; VCEP specifications version 1; 02/11/2022)
Met criteria codes
PP3
REVEL = 0.868 >0.75; no predicted splice impact
PS4_Moderate
2 pts: 2 unrelated probands each with PPB and other DICER1-related phenotypes (PMIDs: 26925222, 26475046)
PM1
Putative missense variants affecting metal ion-binding residues (p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813)
PM2_Supporting
Allele is absent from gnomAD with >20x coverage in the region.
PS2_Very Strong
Confirmed de novo (constitutional mosaicism) in 2 probands with high-specificity phenotypes. (PMIDs: 26925222, 26475046)
PS3_Supporting
In vitro cleavage assays show impaired 5p cleavage (PMIDs: 22187960, 26545620)
Not Met criteria codes
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Code NA for germline variants in hotspot codons
PM5
Multiple other variants in same codon but none are VCEP-curated yet and mostly somatic. ClinVar variation IDs: 933032, 933031, 933030, 932992, 690453, 477242, 932994, 932993
BA1
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
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
BP4
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
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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