Variant classification summary

NM_177438.3:c.4680G>A

DICER1 · NP_803187.1:p.(Ala1560=) · NM_177438.3

GRCh37: chr14:95562577 C>T · GRCh38: chr14:95096240 C>T

Gene: DICER1 Transcript: NM_177438.3

Final call

Benign

BA1 stand-alone benign BS1 strong BS2 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.3

Protein

NP_803187.1:p.(Ala1560=)

gnomAD AF

0.006310387296458104 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The DICER1 c.4680G>A (p.Ala1560=) variant has been reported in ClinVar with benign classifications from multiple clinical laboratories.

2

This variant is common in population databases, including gnomAD v4.1 with total allele frequency 0.00631 and African/African American allele frequency 0.11919, which is well above the DICER1 BA1 threshold of 0.003; gnomAD-Canada also shows allele frequency 0.00863 with 11 homozygotes.

3

Computational data do not support a splice-disrupting effect, with SpliceAI max delta score 0.01, and the REVEL score is 0.07.

Final determination: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4.0 v1.4.0 point-based framework yields a total score of -13, which maps to Benign under the specified Tavtigian-style ranges.

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	This synonymous variant does not fall into the DICER1 loss-of-function categories used for PVS1, and the variant-level PVS1 review did not identify a nonsense, frameshift, or canonical +/-1,2 splice mechanism.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No pathogenic same-amino-acid comparator identified for this synonymous change, so PS1 is not supported.	cspec
PS2	Not assessed	No confirmed de novo data were identified for this variant, so PS2 cannot be assessed.	cspec
PS3	Not assessed	No RNA assay or other DICER1-validated functional assay was identified showing an abnormal effect for this variant, so PS3 is not met.	cspec spliceai
PS4	Not assessed	No case-level phenotype point data were identified to show enrichment in individuals with DICER1-related disease, so PS4 cannot be applied.	cspec clinvar
PM1	N/A	This variant is synonymous and is not a missense change at a DICER1 RNase IIIb hotspot residue or elsewhere in the RNase IIIb missense domain used for PM1.	cspec
PM2	Not met	Population frequency is far above the DICER1 PM2 threshold of <0.000005. In gnomAD v4.1, the total allele frequency is 0.00631 and the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles).	cspec gnomad_v4
PM3	N/A	PM3 is marked not applicable in the DICER1 specification.	cspec
PM4	N/A	This variant is not an in-frame insertion or deletion, so PM4 does not apply.	cspec
PM5	N/A	The DICER1 PM5 rule is classic same-residue missense logic, and this variant is not missense-like, so PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	PM6 is marked not applicable in the DICER1 specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec
PP2	N/A	PP2 is marked not applicable in the DICER1 specification.	cspec
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, and the REVEL score is 0.07, well below the DICER1 PP3 missense threshold of >=0.750.	cspec spliceai revel
PP4	Not assessed	No tumor testing evidence was identified showing a qualifying DICER1 hotspot second hit with retention of this germline variant, so PP4 cannot be applied.	cspec hotspots
PP5	N/A	PP5 is marked not applicable in the DICER1 specification.	cspec
BA1	Met	Population frequency exceeds the DICER1 BA1 threshold of >0.003 in a qualifying gnomAD subpopulation. In gnomAD v4.1, the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles), which is far above the 0.003 threshold and includes far more than 5 alleles with >2000 alleles tested.	cspec gnomad_v4
BS1	Met	Population frequency exceeds the DICER1 BS1 threshold of >0.0003 in a qualifying gnomAD subpopulation. In gnomAD v4.1, the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles), which is far above the 0.0003 threshold.	cspec gnomad_v4
BS2	Met	This variant is observed in homozygous state in population datasets lacking detailed clinical information, which supports BS2 at the supporting level under the DICER1 specification. gnomAD v4.1 reports 596 homozygotes, gnomAD v2.1 reports 195 homozygotes, and gnomAD-Canada reports 11 homozygotes.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	No RNA study was identified showing no splicing impact for this synonymous variant, so BS3 cannot be applied.	cspec spliceai
BS4	Not assessed	No segregation data were identified showing the variant absent in phenotype-positive relatives, so BS4 cannot be assessed.	cspec
BP1	N/A	BP1 is marked not applicable in the DICER1 specification.	cspec
BP2	Not assessed	No co-occurrence or phase data were identified to support BP2.	cspec
BP3	N/A	BP3 is marked not applicable in the DICER1 specification.	cspec
BP4	Not assessed	Available computational evidence argues against a splice-disrupting effect, with SpliceAI max delta score 0.01 and REVEL 0.07, but the DICER1 specification for synonymous/non-coding BP4 calls for concordance of MaxEntScan and SpliceAI. MaxEntScan output was not identified, so BP4 was not fully established.	cspec spliceai revel
BP5	N/A	BP5 is marked not applicable in the DICER1 specification.	cspec
BP6	N/A	BP6 is marked not applicable in the DICER1 specification.	cspec
BP7	Not assessed	This is a synonymous variant, but the DICER1 BP7 rule requires BP4 and also no evidence that the nucleotide is highly conserved. BP4 was not fully established because the required MaxEntScan result was not identified, and no conservation assessment was identified.	cspec spliceai revel

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