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]
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Variant: NM_177438.3(DICER1):c.4740G>T (p.Gln1580His)

CA7330808

412159 (ClinVar)

Gene: DICER1
Condition: dicer1 syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 224f593c-8526-4d0f-a007-75e099474310
Approved on: 2022-10-25
Published on: 2022-11-03

HGVS expressions

NM_177438.3:c.4740G>T
NM_177438.3(DICER1):c.4740G>T (p.Gln1580His)
NC_000014.9:g.95096180C>A
CM000676.2:g.95096180C>A
NC_000014.8:g.95562517C>A
CM000676.1:g.95562517C>A
NC_000014.7:g.94632270C>A
NG_016311.1:g.66243G>T
ENST00000343455.8:c.4740G>T
ENST00000393063.6:c.4740G>T
ENST00000526495.6:c.4740G>T
ENST00000532939.3:c.4740G>T
ENST00000556045.6:c.4740G>T
ENST00000675540.1:n.2485G>T
ENST00000675995.1:c.*3056G>T
ENST00000343455.7:c.4740G>T
ENST00000393063.5:c.4740G>T
ENST00000526495.5:c.4740G>T
ENST00000527414.5:c.4740G>T
ENST00000532939.2:n.775G>T
ENST00000541352.5:c.4740G>T
ENST00000556045.5:c.1434G>T
NM_001195573.1:c.4740G>T
NM_001271282.2:c.4740G>T
NM_001291628.1:c.4740G>T
NM_030621.4:c.4740G>T
NM_177438.2:c.4740G>T
NM_001271282.3:c.4740G>T
NM_001291628.2:c.4740G>T
NM_001395677.1:c.4740G>T
NM_001395678.1:c.4740G>T
NM_001395679.1:c.4740G>T
NM_001395680.1:c.4740G>T
NM_001395682.1:c.4740G>T
NM_001395683.1:c.4740G>T
NM_001395684.1:c.4740G>T
NM_001395685.1:c.4740G>T
NM_001395686.1:c.4458G>T
NM_001395687.1:c.4335G>T
NM_001395688.1:c.4335G>T
NM_001395689.1:c.4335G>T
NM_001395690.1:c.4335G>T
NM_001395691.1:c.4173G>T
NM_001395692.1:c.4740G>T
NM_001395693.1:c.4740G>T
NM_001395694.1:c.4740G>T
NM_001395695.1:c.4740G>T
NM_001395696.1:c.4335G>T
NM_001395697.1:c.3057G>T
NR_172715.1:n.5158G>T
NR_172716.1:n.5342G>T
NR_172717.1:n.5252G>T
NR_172718.1:n.5175G>T
NR_172719.1:n.5008G>T
NR_172720.1:n.5085G>T

Likely Benign

Met criteria codes 2
BS2_Supporting BS3_Supporting
Not Met criteria codes 15
BP4 PVS1 BP7 BP5 PS3 PS4 PS1 PP4 PP3 PM2 PM5 PM4 PM1 BA1 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
The NM_177438.2:c.4740G>T variant in DICER1 is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 1580 (p.Gln1580His). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors/GTRs: 500031, 61756). The highest population minor allele frequency in gnomAD (non-cancer) v2.1.1 is 0.00003 (3/102668 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). 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 (BS3_Supporting; Wu 2018, McGill University). The computational predictor REVEL gives a score of 0.696, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function. In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BS3_Supporting. (Bayesian Points: -2; VCEP specifications version 1.1.0; 10/25/2022)
Met criteria codes
BS2_Supporting
This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors/GTRs: 500031, 61756).
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 (BS3_Supporting; Wu 2018, McGill University).
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.696, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
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
PS4
This variant received a total of 0 phenotype points in a single proband. The phenotype was testicular seminoma (PS4 not met; PMIDs: 21266384, 23547758, 24136150, 24708902, 29762508).
PS1
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
The computational predictor REVEL gives a score of 0.696, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function.
PM2
The highest population minor allele frequency in gnomAD (non-cancer) v2.1.1 is 0.00003 (3/102668 alleles) in the 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
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met).
BA1
The highest population minor allele frequency in gnomAD (non-cancer) v2.1.1 is 0.00003 (3/102668 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
BS1
The highest population minor allele frequency in gnomAD (non-cancer) v2.1.1 is 0.00003 (3/102668 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
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