rs137852977

Positions:

• chr14-95117624-C-A
• chr14-95117624-C-G

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.1507G>T​(p.Glu503*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9870
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.81

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 14-95117624-C-A is Pathogenic according to our data. Variant chr14-95117624-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95117624-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.1507G>T	p.Glu503*	stop_gained, splice_region_variant	9/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.1507G>T	p.Glu503*	stop_gained, splice_region_variant	9/27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2018	This sequence change creates a premature translational stop signal (p.Glu503*) in the DICER1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with pleuropulmonary blastoma or Sertoli-Leydig cell tumor (PMID: 19556464, 24708902, 26925222). This variant is also known as 1689G>T (E493X) in the literature. ClinVar contains an entry for this variant (Variation ID: 4469). Loss-of-function variants in DICER1 are known to be pathogenic (PMID: 19556464, 21266384). For these reasons, this variant has been classified as Pathogenic. -
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	International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota	Nov 10, 2014	- -

Pleuropulmonary blastoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 21, 2009

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2023

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 (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 25451712, 24708902, 19556464, 28654427, 21266384, 30178239, 24839956, 23728841, 21501861, 26925222, 30339877) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2013

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	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.96
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.0		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: rs137852977; hg19: chr14-95583961;