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 ClinVar but not with the Allele Registry data

Variant: NM_177438.3(DICER1):c.5515C>T (p.Arg1839Trp)

479634 (ClinVar)

Gene: DICER1
Condition: dicer1 syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b1bd01ae-8a55-4501-acbc-f73bb1c52494
Approved on: 2023-04-25
Published on: 2023-05-12

HGVS expressions

NM_177438.3:c.5515C>T
NM_177438.3(DICER1):c.5515C>T (p.Arg1839Trp)

Uncertain Significance

Met criteria codes 2
BP4 PM1_Supporting
Not Met criteria codes 15
BS3 BS4 BS1 BS2 BP2 PS3 PS2 PS4 PS1 BA1 PP4 PP1 PP3 PM5 PM2

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 1.1.0

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.5515C>T variant in DICER1 is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 1839 (p.Arg1839Trp). The highest population minor allele frequency in gnomAD v3.1.2 is 0.0002094 (1/4776 alleles) in the South Asian subpopulation (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.398, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). 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). Due to conflicting evidence, this variant is classified as a variant of unknown significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4, PM1_Supporting. (Bayesian Points: 0; VCEP specifications version v1.1; 04/25/2023)
Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.398, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4).
PM1_Supporting
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).
Not Met criteria codes
BS3
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Has been observed in 9 unrelated females without tumors through age 50 (Internal lab contributor, SCV000661969.4)
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 different missense variants, c.5516G>A (p.Arg1839Gln) and c.5515C>G (p.Arg1839Gly), in the same codon have been reported in patients with DICER1 syndrome (ClinVar Variation IDs: 133976, 1497494. However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).
PM2
The highest population minor allele frequency in gnomAD v3.1.2 is 0.0002094 (1/4776 alleles) in the South Asian subpopulation (PM2_Supporting, BS1, and BA1 are not met).
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.