The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]


Variant: NM_177438.2(DICER1):c.5276A>G (p.Lys1759Arg)

CA158282

133974 (ClinVar)

Gene: DICER1
Condition: dicer1 syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 13d61f90-d123-45d2-ac7d-9354e09e66d5
Approved on: 2022-05-18
Published on: 2022-07-08

HGVS expressions

NM_177438.2:c.5276A>G
NM_177438.2(DICER1):c.5276A>G (p.Lys1759Arg)
NC_000014.9:g.95093976T>C
CM000676.2:g.95093976T>C
NC_000014.8:g.95560313T>C
CM000676.1:g.95560313T>C
NC_000014.7:g.94630066T>C
NG_016311.1:g.68447A>G
ENST00000343455.8:c.5276A>G
ENST00000393063.6:c.5276A>G
ENST00000526495.6:c.5276A>G
ENST00000556045.6:c.5276A>G
ENST00000675540.1:n.3021A>G
ENST00000675995.1:c.*3592A>G
ENST00000343455.7:c.5276A>G
ENST00000393063.5:c.5276A>G
ENST00000526495.5:c.5276A>G
ENST00000527414.5:c.5276A>G
ENST00000541352.5:c.5276A>G
ENST00000556045.5:c.1970A>G
NM_001195573.1:c.5276A>G
NM_001271282.2:c.5276A>G
NM_001291628.1:c.5276A>G
NM_030621.4:c.5276A>G
NM_001271282.3:c.5276A>G
NM_001291628.2:c.5276A>G
NM_177438.3:c.5276A>G
NM_001395677.1:c.5276A>G
NM_001395678.1:c.5276A>G
NM_001395679.1:c.5276A>G
NM_001395680.1:c.5276A>G
NM_001395682.1:c.5276A>G
NM_001395683.1:c.5276A>G
NM_001395684.1:c.5276A>G
NM_001395685.1:c.5276A>G
NM_001395686.1:c.4994A>G
NM_001395687.1:c.4871A>G
NM_001395688.1:c.4871A>G
NM_001395689.1:c.4871A>G
NM_001395690.1:c.4871A>G
NM_001395691.1:c.4709A>G
NM_001395697.1:c.3593A>G
NR_172715.1:n.5694A>G
NR_172716.1:n.5878A>G
NR_172717.1:n.5788A>G
NR_172718.1:n.5711A>G
NR_172719.1:n.5544A>G
NR_172720.1:n.5621A>G
NM_177438.3(DICER1):c.5276A>G (p.Lys1759Arg)
More

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 3
PM1_Supporting BS2 BP4
Not Met criteria codes 15
PP1 PP4 PP3 PM6 PM2 PM5 BA1 BS4 BS3 BS1 BP2 PS2 PS4 PS3 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

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.5276A>G variant in DICER1 is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 1759 (p.Lys1759Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001071 in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors: 61756, 500031). The computational predictor REVEL gives a score of 0.444, 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, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID: 31342592)(PM1_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: (BS2, BP4, PM1_Supporting). (Bayesian Points: -4; VCEP specifications version 1; 02/11/2022).
Met criteria codes
PM1_Supporting
This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID: 31342592)(PM1_Supporting).
BS2
This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors: 61756, 500031).
BP4
The computational predictor REVEL gives a score of 0.444, 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).
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.01071% in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
PM5
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
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
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
Curation History
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