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]
Link to SEPIO compliant JSON-LD document

Variant: NM_177438.2(DICER1):c.2614G>A (p.Ala872Thr)

CA158264

133967 (ClinVar)

Gene: DICER1
Condition: dicer1 syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d0180ab5-21d7-45b9-bb2f-91f305099d4f
Approved on: 2022-05-18
Published on: 2022-07-08

HGVS expressions

NM_177438.2:c.2614G>A
NM_177438.2(DICER1):c.2614G>A (p.Ala872Thr)
NC_000014.9:g.95107916C>T
CM000676.2:g.95107916C>T
NC_000014.8:g.95574253C>T
CM000676.1:g.95574253C>T
NC_000014.7:g.94644006C>T
NG_016311.1:g.54507G>A
ENST00000343455.8:c.2614G>A
ENST00000393063.6:c.2614G>A
ENST00000526495.6:c.2614G>A
ENST00000532939.3:c.2614G>A
ENST00000556045.6:c.2614G>A
ENST00000675540.1:n.436G>A
ENST00000675995.1:c.*930G>A
ENST00000343455.7:c.2614G>A
ENST00000393063.5:c.2614G>A
ENST00000526495.5:c.2614G>A
ENST00000527414.5:c.2614G>A
ENST00000541352.5:c.2614G>A
NM_001195573.1:c.2614G>A
NM_001271282.2:c.2614G>A
NM_001291628.1:c.2614G>A
NM_030621.4:c.2614G>A
NM_001271282.3:c.2614G>A
NM_001291628.2:c.2614G>A
NM_177438.3:c.2614G>A
NM_001395677.1:c.2614G>A
NM_001395678.1:c.2614G>A
NM_001395679.1:c.2614G>A
NM_001395680.1:c.2614G>A
NM_001395682.1:c.2614G>A
NM_001395683.1:c.2614G>A
NM_001395684.1:c.2614G>A
NM_001395685.1:c.2614G>A
NM_001395686.1:c.2332G>A
NM_001395687.1:c.2209G>A
NM_001395688.1:c.2209G>A
NM_001395689.1:c.2209G>A
NM_001395690.1:c.2209G>A
NM_001395691.1:c.2047G>A
NM_001395692.1:c.2614G>A
NM_001395693.1:c.2614G>A
NM_001395694.1:c.2614G>A
NM_001395695.1:c.2614G>A
NM_001395696.1:c.2209G>A
NM_001395697.1:c.931G>A
NR_172715.1:n.3032G>A
NR_172716.1:n.2959G>A
NR_172717.1:n.3126G>A
NR_172718.1:n.3126G>A
NR_172719.1:n.2959G>A
NR_172720.1:n.2959G>A
NM_177438.3(DICER1):c.2614G>A (p.Ala872Thr)

Benign

Met criteria codes 4
BP4 BS2 BS1 BS3_Supporting
Not Met criteria codes 14
PP1 PP4 PP3 PM1 PM5 PM6 PM2 PS2 PS4 PS3 PS1 BA1 BP2 BS4

Evidence Links 1

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

PDF
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.2614G>A (p.Ala872Thr) variant in DICER1 has the highest population minor allele frequency in gnomAD v2.1.1 is 0.00119 in non-Finnish European population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (Internal lab contributors: 61756, 500031) and has been observed in a homozygous state in 5 healthy individuals (Internal lab contributors: 26957, 500031)(BS2). In vitro cleavage assay in HEK293 cells showed that this variant produces both 5p and 3p microRNAs from a pre-miRNA, indicating that this variant is unlikely to impact protein function (PMID: 31342592)(BS3_Supporting). The computational predictor REVEL gives a score of 0.488, 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). In summary, this variant meets the criteria to be classified as benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2, BS3_Supporting, BP4. (Bayesian Points: -10; VCEP specifications version 1; 02/11/2022).
Met criteria codes
BP4
Revel score = 0.488
BS2
This variant has been observed in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (Internal lab contributors: 61756, 500031) and has been observed in a homozygous state in 5 healthy individuals (Internal lab contributors: 26957, 500031)(BS2).
BS1
Gnomad (NFE): 0.119% (153/128848)
BS3_Supporting
In vitro cleavage assay in HEK293 cells showed that this variant produces both 5p and 3p microRNAs from a pre-miRNA, indicating that this variant is unlikely to impact protein function (PMID: 31342592)(BS3_Supporting).
In vitro cleavage assay determined that p.A872T cleaves precursor‐miRNA‐122 as efficiently as wild‐type DICER1. Variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed) PubMed:31342592
Not Met criteria codes
PP1
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
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
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
PS3
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
BP2
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
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.