14-95105111-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_177438.3(DICER1):c.3229G>A(p.Asp1077Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1077H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 6.13

Publications

3 publications found

Variant links:

Genes affected

DICER1 (HGNC:17098): (dicer 1, ribonuclease III) This gene encodes a protein possessing an RNA helicase motif containing a DEXH box in its amino terminus and an RNA motif in the carboxy terminus. The encoded protein functions as a ribonuclease and is required by the RNA interference and small temporal RNA (stRNA) pathways to produce the active small RNA component that represses gene expression. This protein also acts as a strong antiviral agent with activity against RNA viruses, including the Zika and SARS-CoV-2 viruses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2021]

DICER1 Gene-Disease associations (from GenCC):

DICER1-related tumor predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pleuropulmonary blastoma
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
DICER1 syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

DICER1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2601798).

BP6

Variant 14-95105111-C-T is Benign according to our data. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643. Variant chr14-95105111-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 543643.

BS2

High AC in GnomAdExome4 at 9 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3 link	c.3229G>A	p.Asp1077Asn	missense_variant	Exon 20 of 27	ENST00000343455.8	NP_803187.1	Q9UPY3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 link	c.3229G>A	p.Asp1077Asn	missense_variant	Exon 20 of 27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251358

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111968

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DICER1-related disorder

Uncertain:1

Oct 19, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DICER1 c.3229G>A variant is predicted to result in the amino acid substitution p.Asp1077Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 4 of ~283,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/14-95571448-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/543643/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Pleuropulmonary blastoma

Uncertain:1

Jun 15, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DICER1 c.3229G>A (p.Asp1077Asn) missense change has an overall frequency of 0.001118% in gnomAD non-cancer v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function and no splicing effects are predicted, but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with DICER1-associated tumors. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided

Uncertain:1

Jan 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DICER1 c.3229G>A (p.Asp1077Asn) variant has not been reported in individuals with DICER1-related conditions in the published literature. The frequency of this variant in the general population, 0.000014 (4/282760 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

DICER1-related tumor predisposition

Uncertain:1

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1077 of the DICER1 protein (p.Asp1077Asn). This variant is present in population databases (rs373412959, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 543643). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Ovarian cancer

Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Apr 18, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;T;T;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;.;D;.;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

L;L;L;L;L

PhyloP100

6.1

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.8

N;N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.014

D;D;D;D;D

Sift4G

Uncertain

0.043

D;D;D;D;T

Polyphen

0.82

P;P;P;P;.

Vest4

0.35

MVP

0.68

MPC

0.86

ClinPred

0.53

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.72

Mutation Taster

=225/75

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over