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

CA7330808

412159 (ClinVar)

Gene: DICER1

Condition: dicer1 syndrome

Inheritance Mode: Autosomal dominant inheritance

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: BS2_Supporting BS3_Supporting

• Not Met criteria codes: BA1 PM5 PM4 PM1 PM2 BS1 BP4 BP7 BP5 PVS1 PS3 PS4 PS1 PP4 PP3

Expert Panel

DICER1 and miRNA-Processing Gene VCEP

Criteria Specification Information

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

• 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).
• 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).
• 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).
• 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).
• 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.
• 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
• PVS1: 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.