DICER1 c.2337A>G, p.Thr779=
NM_177438.3:c.2337A>G
Likely Benign
This synonymous DICER1 variant shows no evidence of protein or splicing impact and is supported by benign computational (BP4), reputable source (BP6), and silent variant (BP7) criteria, leading to a Likely Benign classification.
ACMG/AMP Criteria Applied
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
DICER1
Transcript
NM_177438.3
MANE Select
Total Exons
27
Strand
Reverse (−)
Reference Sequence
NC_000014.8
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_177438.2 | RefSeq Select | 27 exons | Reverse |
| NM_177438.1 | Alternative | 27 exons | Reverse |
Variant Details
HGVS Notation
NM_177438.3:c.2337A>G
Protein Change
T779=
Location
Exon 15
(Exon 15 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_177438.3
Genome Browser
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HGVS InputNM_177438:c.2337A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0046%
Rare
Highest in Population
European (non-Finnish)
0.0093%
Rare
Global: 0.0046%
European (non-Finnish): 0.0093%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282734Alt: 13Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0046%, 13/282734 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.0093%, 12/129064 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
5 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.31
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for PVS1: 'Nonsense or frameshift variants: PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.' The evidence for this variant shows it is a synonymous (T779=) change with no impact on protein sequence or NMD. Therefore, this criterion is not applied because the variant type does not meet PVS1 requirements.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1: 'Strong For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI).' The evidence for this variant shows no amino acid change (synonymous). Therefore, this criterion is not applied because there is no amino acid change to compare.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS2: 'Very Strong Strength for confirmed de novo occurrence with paternity and maternity confirmed.' The evidence for this variant shows no de novo inheritance data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines for PS3: 'Strong RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption.' The evidence for this variant shows no RNA assay or functional data. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS4: 'Strong evidence from case-control or phenotype data (≥4 phenotype points).' The evidence for this variant shows no case or phenotypic data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PM1: 'Moderate Putative missense variants at residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813.' The evidence for this variant shows it is synonymous and not a missense at those codons. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines for PM2: 'Supporting Allele frequency <0.000005 across gnomAD with no more than one allele in any subpopulation and at least 20× coverage.' The evidence for this variant shows a MAF of 0.0093% in European (non-Finnish) and 0.0046% overall, which exceeds 0.000005. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM3: 'Moderate evidence for variants detected in trans with a pathogenic variant in recessive disorders.' The evidence for this variant shows no trans observations with a P/LP DICER1 variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines for PM4: 'Moderate In-frame indels with a residue within the RNase IIIb domain (p.Y1682–p.S1846).' The evidence for this variant shows it is synonymous, not an indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5: 'Moderate Missense variant under evaluation should have equal or worse Grantham score than a known pathogenic variant.' The evidence for this variant shows it is synonymous. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM6: 'Supporting evidence for assumed de novo without confirmation of paternity and maternity.' The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PP1: 'Supporting 3–4 meioses across ≥1 family.' The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP2: 'Supporting for missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease.' The evidence for this variant shows it is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for PP3: 'Supporting for missense variants, REVEL ≥0.75 OR splicing predictors predict splicing effects.' The evidence for this variant shows SpliceAI predicts minimal impact (max score 0.09) and no pathogenic computational signals. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for PP4: 'Supporting Somatic tumor testing identifies a somatic hotspot second hit.' The evidence for this variant shows no tumor testing data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP5: 'Supporting Reputable source reports variant as pathogenic but evidence not available.' The evidence for this variant shows only benign reports in ClinVar. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1: 'Stand Alone Frequency >0.003 (0.3%) in gnomAD subpopulations.' The evidence for this variant shows a maximum frequency of 0.0093% in a subpopulation, which is below 0.3%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: 'Strong Frequency >0.0003 (0.03%) in gnomAD subpopulations.' The evidence for this variant shows a maximum frequency of 0.0093% in a subpopulation, which exceeds 0.0003, but BS1 requires >0.0003; our frequency is 0.000093, below threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2: 'Strong evidence from 40+ unrelated tumor-free females or homozygosity in healthy individuals.' The evidence for this variant shows no homozygotes and no tumor-free cohort. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3: 'Strong For intronic or synonymous variants, no splicing impact observed via RNA assay.' The evidence for this variant shows only in silico splicing predictions, no RNA assay. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines for BS4: 'Strong lack of segregation in affected family members.' The evidence for this variant shows no family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP1: 'Supporting for missense variant in a gene where only LOF causes disease.' The evidence for this variant shows it is synonymous. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines for BP2: 'Supporting ≥1 observation in trans with P/LP DICER1 variant or ≥3 observations in cis with 2+ different P/LP variants.' The evidence for this variant shows no trans or cis observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP3: 'Supporting for in-frame indels in repetitive regions.' The evidence for this variant shows it is synonymous, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines for BP4: 'Supporting for synonymous/intronic variants concordance of MaxEntScan and SpliceAI indicating no splicing effects.' The evidence for this variant shows SpliceAI predicts minimal impact on splicing (max score 0.09). Therefore, this criterion is applied at Supporting strength because the in silico predictors concordantly indicate no splicing impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP5: 'Supporting variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows no alternate molecular basis in reported cases. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines for BP6: 'Supporting Reputable source reports variant as benign but evidence not available.' The evidence for this variant shows five clinical laboratories in ClinVar report it as Likely Benign without shared primary data. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
According to standard ACMG guidelines for BP7: 'Supporting Silent variant OR intronic variant at or beyond +7/-21 positions when BP4 is met.' The evidence for this variant shows it is a silent change (T779=) and BP4 is met. Therefore, this criterion is applied at Supporting strength.