Variant classification summary

NM_177438.3:c.3827A>G

DICER1 · NP_803187.1:p.(Asp1276Gly) · NM_177438.3

GRCh37: chr14:95569906 T>C · GRCh38: chr14:95103569 T>C

Gene: DICER1 Transcript: NM_177438.3

Final call

VUS

Variant details

Gene

DICER1

Transcript

NM_177438.3

Protein

NP_803187.1:p.(Asp1276Gly)

gnomAD AF

4.336594039041737e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1, PM4, and BP3 are all not applicable under the DICER1 VCEP rules because this is a missense substitution rather than a loss-of-function, in-frame-indel, or repeat-region deletion event.

2

For p.Asp1276Gly, the DICER1 VCEP's codon/residue/domain criteria provide no positive evidence: PS1 and PM5 lack qualifying pathogenic same-residue comparators, PM1 excludes residue 1276, and PP2/BP1 are not applicable by specification.

3

Within the requested group, PP5, BP5, and BP6 are excluded by the governing DICER1 VCEP; PS4 and PP4 remain applicable in principle but cannot be assessed because their required variant-specific phenotype or tumor evidence is absent.

4

PP3 and BP4 are not_assessed because the missense REVEL branches can be evaluated, but the VCEP-required splicing-predictor concordance cannot be established without MaxEntScan.

5

BP7 is not_applicable because the variant is missense and outside the VCEP-defined BP7 scope.

Final determination: Under the DICER1 VCEP Version 1.4 point-based framework, a total score of 0 falls within the -1 to 5 point range for Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: the VCEP PVS1 rule covers nonsense, frameshift, splice-site, deletion, duplication, and initiation-codon events, not this exon 21 missense variant.	cspec vcep_pvs1_decisiontree pvs1_variant_assessment
PS1	Not met	Not met: zero same-amino-acid pathogenic ClinGen DICER1 VCEP comparator variants were identified for p.Asp1276Gly.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no documented de novo observation, parental maternity and paternity confirmation, or de novo-point tally is available.	cspec
PS3	Not assessed	Not assessed: no variant-specific RNA splicing or in vitro pre-miRNA cleavage assay with the VCEP-required controls is available.	cspec
PS4	Not assessed	Not assessed: no phenotype-point assignments, variant-specific case-control counts, or verified literature observation are available for c.3827A>G.	cspec
PM1	Not met	Not met: residue 1276 is outside the VCEP's seven metal-binding residues and the RNase IIIb PM1 interval p.Tyr1682-Ser1846.	cspec
PM2	Not met	Not met: although gnomAD v4.1 total AF is 4.34e-06, the VCEP's one-allele-per-subpopulation limit is exceeded, including 6 NFE alleles.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the DICER1 VCEP explicitly marks PM3 as not applicable.	cspec
PM4	N/A	Not applicable: c.3827A>G is a missense substitution with no protein-length change, whereas VCEP PM4 requires an in-frame indel.	cspec pvs1_variant_assessment
PM5	Not met	Not met: zero same-residue comparator variants were collected, so no pathogenic ClinGen DICER1 VCEP variant supports PM5 at residue 1276.	cspec pm5_candidates
PM6	N/A	Not applicable: the VCEP directs users to use PS2 instead of PM6 for de novo evidence.	cspec
PP1	Not assessed	Not assessed: no phenotype-positive relatives, genotype results, family count, or meiosis count is documented.	cspec
PP2	N/A	Not applicable: the DICER1 VCEP excludes PP2 because benign and likely benign missense variants occur throughout the gene.	cspec
PP3	Not assessed	Not assessed: REVEL 0.104 is below the ≥0.750 PP3 threshold, while the required concordant splicing-predictor result lacks a MaxEntScan value.	cspec revel spliceai
PP4	Not assessed	Not assessed: required tumor evidence of an RNase IIIb hotspot second hit, germline retention, and no additional non-hotspot DICER1 variants is unavailable.	cspec
PP5	N/A	Not applicable: the DICER1 VCEP explicitly prohibits use of PP5.	cspec
BA1	Not met	Not met: the highest gnomAD subpopulation frequency is 1.76e-05, far below the VCEP's >0.003 BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest gnomAD subpopulation frequency is 1.76e-05, below the VCEP's >0.0003 BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report zero homozygotes, with no qualifying healthy-female cohort or additional homozygous observations.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific functional assay demonstrates both 5p and 3p microRNA production or absence of splicing impact with required controls.	cspec
BS4	Not assessed	Not assessed: no phenotype-positive, genotype-negative first-, second-, or third-degree relative is documented.	cspec
BP1	N/A	Not applicable: the DICER1 VCEP excludes BP1 because truncating variants cause only a portion of disease in this gene.	cspec
BP2	Not assessed	Not assessed: no documented cis, trans, or phase-unknown observation with the required pathogenic/likely pathogenic DICER1 variants is available.	cspec
BP3	N/A	Not applicable: the DICER1 VCEP explicitly marks BP3 not applicable, and this variant is missense rather than an in-frame deletion in a repeat region.	cspec pvs1_variant_assessment
BP4	Not assessed	Not assessed: REVEL 0.104 meets the <0.500 BP4 threshold, but concordant MaxEntScan and SpliceAI no-impact predictions are incomplete.	cspec revel spliceai
BP5	N/A	Not applicable: the DICER1 VCEP says BP5 should not be used at this time.	cspec
BP6	N/A	Not applicable: the DICER1 VCEP explicitly prohibits use of BP6.	cspec
BP7	N/A	Not applicable: this is a missense variant, whereas BP7 is limited to silent, specified intronic, or other intronic/non-coding variants.	cspec

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