14-95090506-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The NM_177438.3(DICER1):c.5761A>C variant in DICER1 is a missense variant predicted to cause substitution of asparagine by histidine at amino acid 1921 (p.Asn1921His). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.0000006196 (1/1613836 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.152; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 02/25/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7330596/MONDO:0100216/024

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 3.82

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3 link	c.5761A>C	p.Asn1921His	missense_variant	Exon 27 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 link	c.5761A>C	p.Asn1921His	missense_variant	Exon 27 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251378

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Uncertain:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1921 of the DICER1 protein (p.Asn1921His). This variant is present in population databases (rs775077210, gnomAD 0.01%). 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: 644129). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 95%. 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.

Feb 25, 2025

ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_177438.3(DICER1):c.5761A>C variant in DICER1 is a missense variant predicted to cause substitution of asparagine by histidine at amino acid 1921 (p.Asn1921His). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.0000006196 (1/1613836 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.152; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 02/25/2025).

Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome

Uncertain:1

Oct 20, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.N1921H variant (also known as c.5761A>C), located in coding exon 26 of the DICER1 gene, results from an A to C substitution at nucleotide position 5761. The asparagine at codon 1921 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T;T;.

Eigen

Benign

0.051

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.0

.;.;T;.;T

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.34

N;N;N;N;.

PhyloP100

3.8

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.66

N;N;N;N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.038

D;D;D;D;D

Vest4

0.37

ClinPred

0.34

GERP RS

3.6

Varity_R

0.19

gMVP

0.42

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over