rs886037672

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.1525C>T(p.Arg509*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,542 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (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:8

Conservation

PhyloP100: 5.55

Publications

20 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 14-95116680-G-A is Pathogenic according to our data. Variant chr14-95116680-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 254288.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.1525C>T	p.Arg509*	stop_gained	Exon 10 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.1525C>T	p.Arg509*	stop_gained	Exon 10 of 27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111826

Other (OTH)

AF:

0.00

AC:

AN:

60384

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

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

Cov.:

Alfa

AF:

0.0000427

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Pathogenic:4

Dec 19, 2024

Hereditary Cancer Group, L’Institut d'Investigació Biomèdica de Bellvitge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS2, PS4, PM2_supporting, PP4 -

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 -

Nov 11, 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.Arg509*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multinodular goiter (PMID: 23728841, 24839956, 26925222, 27459524). ClinVar contains an entry for this variant (Variation ID: 254288). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Apr 19, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pleuropulmonary blastoma;C1867234:Rhabdomyosarcoma, embryonal, 2

Pathogenic:1

Sep 05, 2024

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Null variant (nonsense) in gene DICER1, predicted to cause NMD. Loss-of-function is a known mechanism of disease. The exon contains 25 pathogenic variants. The truncated region contains 550 pathogenic variants (PVS1). Combined evidence strength is Very Strong (score = 9).Very Strong: ClinVar classifies this variant as Pathogenic, 2 stars associated with Global Developmental Delay - Lung Cysts - Overgrowth - Wilms Tumor Syndrome.Supporting: LOVD classifies this variant as Pathogenic (PP5). Variant not found in gnomAD genomes, good gnomAD genomes coverage = 31.0.GnomAD exomes allele count = 1 is less than 5 for AD gene DICER1 (PM2). 23-year-old female patient, with the presence of pancreatic cyst in childhood, pulmonary bullae and a high-grade fusocellular stromal neoplasm of the uterine cervix, compatible with embryonal rhabdomyosarcoma in adulthood. In addition, a heterozygous germline pathogenic variant of the DICER1 gene was identified. -

not provided

Pathogenic:1

Feb 23, 2018

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Mar 10, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R509* pathogenic mutation (also known as c.1525C>T), located in coding exon 9 of the DICER1 gene, results from a C to T substitution at nucleotide position 1525. This changes the amino acid from an arginine to a stop codon within coding exon 9. This variant was reported in individual(s) with features consistent with DICER1-related tumor predisposition syndrome (Darrat I et al. Head Neck, 2013 Dec;35:E369-71; de Kock L et al. Acta Neuropathol, 2014 Jul;128:111-22; Khan NE et al. Pediatr Nephrol, 2018 Dec;33:2281-2288; Dural O et al. J Pediatr Adolesc Gynecol, 2020 Apr;33:173-176). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.97

PhyloP100

5.6

Vest4

0.99

GERP RS

3.1

Mutation Taster

=0/200

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over