rs886037672

Variant names:

• chr14-95116680-G-A
• rs886037672
• NM_177438.3:c.1525C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95116680-G-A
• chr14-95116680-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.55

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]

ACMG classification

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 rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.1525C>T	p.Arg509*	stop_gained	Exon 10 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.1525C>T	p.Arg509*	stop_gained	Exon 10 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461542 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727076

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:4

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. -

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 -

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

Jan 31, 2022

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 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	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
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

Other links and lift over

dbSNP: rs886037672; hg19: chr14-95583017; COSMIC: COSV58621515;