rs886037684

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_177438.3(DICER1):c.2062C>T(p.Arg688*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R688R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DICER1
NM_177438.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 3.28

Publications

10 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-95112226-G-A is Pathogenic according to our data. Variant chr14-95112226-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 254303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3 link	c.2062C>T	p.Arg688*	stop_gained	Exon 13 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.2062C>T	p.Arg688*	stop_gained	Exon 13 of 27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727168

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111912

Other (OTH)

AF:

0.00

AC:

AN:

60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Pathogenic:5

Nov 10, 2014

International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2019

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

ACMG criteria met: PVS1, PM2, PM7, PP4 -

Jan 25, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2013

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in this study maternally inherited in a 1-year-old male with pulmonary pleuroblastoma -

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg688*) in the DICER1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DICER1 are known to be pathogenic (PMID: 19556464, 21266384). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of DICER1 syndrome (PMID: 26822237, 26925222, 26928971, 28323992, 28960912). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254303). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Jan 26, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Nov 22, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26925222, 26461232, 26822237, 26928971, 27697588, 28097783, 28862265, 29762508, 28960912, 28323992) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jan 06, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R688* pathogenic mutation (also known as c.2062C>T), located in coding exon 12 of the DICER1 gene, results from a C to T substitution at nucleotide position 2062. This changes the amino acid from an arginine to a stop codon within coding exon 12. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with DICER1-related disease (Wu MK et al. Pediatr Blood Cancer, 2016 07;63:1272-5; Parsons DW et al. JAMA Oncol, 2016 May;2:616-624; Khan NE et al. J Clin Endocrinol Metab, 2017 05;102:1614-1622; Fita AM et al. Pediatr Blood Cancer, 2017 Aug;64; Brenneman M et al. F1000Res, 2015 Jul;4:214; de Kock L et al. Mod Pathol, 2020 06;33:1207-1219). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Euthyroid goiter;C1266144:Pleuropulmonary blastoma;C1867234:Rhabdomyosarcoma, embryonal, 2

Pathogenic:1

Apr 29, 2025

Institute of Immunology and Genetics Kaiserslautern

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG Criteria: PVS1, PM2, PP5 ; Variant was found in heterozygous state. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.083

FATHMM_MKL

Uncertain

0.91

PhyloP100

3.3

Vest4

0.96

GERP RS

2.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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rs886037684

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