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NM_177438.3:c.4206+9del
p.? · DICER1
ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4 · v1.4
0%
complete
Final classification
Benign
BA1BS1BS2
DICER1
c.4206+9del
p.?
unknown · exon 22i
Gene context NCBI Gene ↗ OncoKB ↗

DICER1 encodes an enzyme that processes RNA into small silencing RNAs and microRNAs, which regulate gene expression after transcription. Germline mutations in DICER1 cause DICER1-related disorders, a familial tumor susceptibility syndrome that increases the risk of pleuropulmonary blastoma, cystic nephroma, rhabdomyosarcoma, multinodular goiter, and ovarian Sertoli-Leydig cell tumors. DICER1 acts as a tumor suppressor, and loss or reduced activity of the protein is linked to cancer development and poorer outcomes in several cancer types, including lung, breast, and ovarian cancers.

This variant

DICER1 acts as a tumor suppressor whose loss of function underlies DICER1-related tumor predisposition. This common intronic deletion (gnomAD v4.1 overall allele frequency 0.352171) has no predicted effect on splicing, and its Benign classification indicates it does not impair DICER1's tumor-suppressor function or raise the cancer risks associated with pathogenic DICER1 variants.

Transcript
NM_177438.3
HGVS · transcript:coding
NM_177438.3:c.4206+9del
GRCh38
chr14:95099770 AC>A
GRCh37
chr14:95566107 AC>A
Benign under the ClinGen DICER1 VCEP version 1.4 framework: BA1 stand-alone benign (-8) + BS1 strong (-4) + BS2 supporting (-1) = -13 points, mapping to Benign.
Classification rationale
BA1BS1BS2 Benign
DICER1 c.4206+9del unknown · exon 22i

BA1 (stand-alone benign): allele frequency above 0.003 in multiple gnomAD v4.1 subpopulations, most strikingly East Asian 0.485669. BS1 (strong): allele frequency above 0.0003 in multiple gnomAD v4.1 subpopulations meeting size and allele-count requirements. BS2 (supporting): thousands of homozygous carriers in gnomAD v4.1. Overall Benign: BA1 (-8) plus BS1 strong (-4) and BS2 supporting (-1) total -13 points, which maps to Benign.

BA1 + BS1 + BS2 → Benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_177438.3 · variants mapped to exon structure
DICER1 NM_177438.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength Supporting Moderate Strong Very strong
BA1 stand-alone Benign
Met (stand-alone benign): gnomAD v4.1 allele frequency exceeds the 0.003 threshold in multiple subpopulations, including East Asian 0.485669 (5524/11374 alleles).
The DICER1 VCEP v1.4 BA1 rule requires frequency >0.003 in a gnomAD subpopulation, with >2,000 alleles tested and at least 5 alleles present.gnomAD v4.1 reports the variant at overall AF 0.352171 (207044/587908 alleles); East Asian AF is 0.485669 (5524/11374 alleles), with 132 homozygotes. Other large subpopulations also substantially exceed the BA1 threshold.
cspec ↗gnomad_v4 ↗
BS1 strong Benign
Met (strong): gnomAD v4.1 allele frequency exceeds the 0.0003 threshold in multiple subpopulations meeting sample-size and allele-count requirements.
The DICER1 VCEP v1.4 BS1 rule requires frequency >0.0003 in a gnomAD subpopulation, with >2,000 alleles tested and at least 5 alleles present.gnomAD v4.1 reports AF 0.352171 overall and AF 0.485669 in East Asian individuals (5524/11374 alleles); the qualifying subpopulation observations are far above the BS1 threshold.
cspec ↗gnomad_v4 ↗
BS2 supporting Benign
Met (supporting): gnomAD v4.1 contains thousands of homozygous observations, far exceeding the required two.
The DICER1 VCEP v1.4 BS2 supporting rule allows 2 or more observations of homozygosity in individuals lacking clinical information.gnomAD v4.1 reports 7262 homozygotes for the variant overall, including 132 in the East Asian subpopulation and substantial homozygote counts in other large subpopulations.
cspec ↗gnomad_v4 ↗
Assessed · not applied · 4 not met · 10 not assessed
Pathogenic
PVS1 Not met: this non-canonical intronic deletion is outside the PVS1 splice-variant entry conditions, and SpliceAI max delta 0.004 predicts no splice impact.
PS2 Not assessed: no proband-level de novo observation with parental genotypes and confirmed maternity and paternity was documented.
PS3 Not assessed: no variant-specific RNA splicing assay or in vitro DICER1 cleavage assay data were available.
PS4 Not assessed: no phenotype-pointed probands, case-control comparison, or exact-variant case series were available from which to assign points.
PM2 Not met: the variant is common in gnomAD v4.1 (overall allele frequency 0.352171), incompatible with PM2 rarity.
PM4 Not met: this intronic deletion with protein consequence p.? is not an in-frame protein indel or stop-loss variant as PM4 requires.
PP1 Not assessed: no affected relatives with documented co-segregating genotypes or countable meioses were available.
PP3 Not met: SpliceAI max delta 0.004 predicts no splicing impact, and no MaxEntScan result is available to show the required concordance.
PP4 Not assessed: no tumor sequencing showed the germline variant retained with a somatic RNase IIIb hotspot second hit.
Benign
BS3 Not assessed: no repeated variant-specific RNA or cleavage assay data demonstrating absence of splicing impact were available.
BS4 Not assessed: no genotype-negative affected relatives or familial genotype results were documented.
BP2 Not assessed: no observations in trans or cis with pathogenic DICER1 variants, or other allelic data, were documented.
BP4 Not assessed: BP4 requires concordant MaxEntScan and SpliceAI predictions of no splicing effect; SpliceAI max delta is 0.004, but no MaxEntScan result is available.
BP7 Not assessed: position +9 meets the BP7 positional requirement, but BP4 must be applied first and cannot be assessed without MaxEntScan.
N/A · 11 PS1 · PM1 · PM3 · PM5 · PM6 · PP2 · PP5 · BP1 · BP3 · BP5 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.352171; MAF= 35.21707%, 207044/587908 alleles, homozygotes = 7262) and has highest observed frequency in the East Asian population (AF= 0.485669; MAF= 48.56691%, 5524/11374 alleles, homozygotes = 132); grpmax FAF= 0.476004.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0327049; MAF= 3.27049%, 7782/237946 alleles, homozygotes = 1125) and has highest observed frequency in the African/African American population (AF= 0.151915; MAF= 15.19154%, 3117/20518 alleles, homozygotes = 543); grpmax FAF= 0.314123.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.46475563909774437, 2967/6384 alleles, homozygotes = 279).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
35% · 207044 / 587,908
7262 hom · FAF 48%
East Asian
5524 / 11,374
49%
132 hom
Admixed American
11239 / 23,246
48%
871 hom
African/African American
21229 / 44,666
48%
2469 hom
South Asian
15875 / 35,160
45%
738 hom
Amish
96 / 224
43%
2 hom
European (Finnish)
6981 / 18,108
39%
325 hom
Remaining individuals
8259 / 22,654
36%
214 hom
Ashkenazi Jewish
3230 / 9,070
36%
87 hom
Middle Eastern
748 / 2,204
34%
30 hom
European (non-Finnish)
133863 / 421,202
32%
2394 hom
gnomAD v2.1
3.3% · 7782 / 237,946
1125 hom · FAF 31%
African/African American
3117 / 20,518
15%
543 hom
European (Finnish)
595 / 18,426
3.2%
55 hom
Remaining individuals
190 / 6,276
3%
15 hom
European (non-Finnish)
2811 / 110,542
2.5%
297 hom
East Asian
317 / 17,502
1.8%
43 hom
Admixed American
437 / 29,630
1.5%
95 hom
Ashkenazi Jewish
86 / 9,046
0.95%
16 hom
South Asian
229 / 26,006
0.88%
61 hom
gnomAD Canada 🇨🇦
46% · 2967 / 6,384
279 hom · FAF 49%
⚠ LCR indel · split
South Asian
336 / 630
53%
40 hom
East Asian
246 / 464
53%
15 hom
African/African American
370 / 720
51%
61 hom
Latino/Admixed American
188 / 374
50%
17 hom
European (non-Finnish)
1542 / 3,494
44%
122 hom
Remaining individuals
161 / 374
43%
15 hom
Middle Eastern
21 / 52
40%
1 hom
Ashkenazi Jewish
102 / 272
38%
8 hom
European (Finnish)
1 / 4
25%
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (2 clinical laboratories). (ClinVarID = 1166424)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV58618229, n = 7 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
8Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 5 PMIDs not cited in assessment
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR
24761742 ↗ DICER1-Related Tumor Predisposition. CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR