Variant rs886037672 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000343455.8(DICER1):c.1525C>T(p.Arg509Ter) 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
ENST00000343455.8 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.55

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 id is 254288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95116680-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.1525C>T	p.Arg509Ter	stop_gained	10/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.1525C>T	p.Arg509Ter	stop_gained	10/27	1	NM_177438.3	ENSP00000343745	P1	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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota	Nov 10, 2014	- -
Pathogenic, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: PVS1, PM2, PM7, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 19, 2023

- -

Pleuropulmonary blastoma;C1867234:Rhabdomyosarcoma, embryonal, 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Sep 05, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2018

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

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 mutation has been observed in multiple individuals with a personal and/or family history that is consistent with DICER1-related disease (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

DANN

Uncertain

0.99

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A;A;A;A

Vest4

0.99

GERP RS

3.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over