rs886037712

Positions:

• chr14-95096607-TAGTC-T

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.4309_4312delGACT​(p.Asp1437fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DICER1 NM_177438.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.45

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 (HGNC:):

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 14-95096607-TAGTC-T is Pathogenic according to our data. Variant chr14-95096607-TAGTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 254332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95096607-TAGTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.4309_4312delGACT	p.Asp1437fs	frameshift_variant	23/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.4309_4312delGACT	p.Asp1437fs	frameshift_variant	23/27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459564 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725914

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: PVS1, PM2, PP1, PP4 -
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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 254332). This premature translational stop signal has been observed in individuals with cystic nephroma and pleuropulmonary blastoma, pituitary blastoma, and embryonal rhabdomyosarcoma (PMID: 21036787, 22180160, 24839956, 26925222). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp1437Metfs*16) 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2018

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2021

The c.4309_4312delGACT pathogenic mutation, located in coding exon 22 of the DICER1 gene, results from a deletion of 4 nucleotides at nucleotide positions 4309 to 4312, causing a translational frameshift with a predicted alternate stop codon (p.D1437Mfs*16). This maternally inherited mutation was detected in siblings diagnosed with cystic nephroma; one brother affected bilaterally also was found to have subtle lung cysts (Bahubeshi A et al. J Med Genet, 2010 Dec;47:863-6; Khan NE et al. Pediatr Nephrol, 2018 Dec;33:2281-2288). This mutation was also reported in a patient with pleuropulmonary blastoma at age 4 and embryonal rhabdomyosarcoma of the cervix and bladder at ages 8 and 12, respectively (Doros L et al. Pediatr Blood Cancer, 2012 Sep;59:558-60). This mutation was identified in an infant with pituitary blastoma and seen in conjunction with a somatic DICER1 mutation (de Kock L et al. Acta Neuropathol, 2014 Jul;128:111-22). 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs886037712; hg19: chr14-95562944;