rs886037692

Variant names:

• chr14-95107663-C-A
• rs886037692
• NM_177438.3:c.2749G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95107663-C-A
• chr14-95107663-C-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_177438.3(DICER1):​c.2749G>T​(p.Glu917*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E917E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.08
• Publications: 2 publications found

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)

ACMG classification

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 14-95107663-C-A is Pathogenic according to our data. Variant chr14-95107663-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 254311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.2749G>T	p.Glu917*	stop_gained	Exon 17 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.2749G>T	p.Glu917*	stop_gained	Exon 17 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.2749G>T	p.Glu917*	stop_gained	Exon 17 of 27	NP_001278557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.2749G>T	p.Glu917*	stop_gained	Exon 17 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.2749G>T	p.Glu917*	stop_gained	Exon 19 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.2749G>T	p.Glu917*	stop_gained	Exon 17 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:2

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, 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

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 28, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E917* pathogenic mutation (also known as c.2749G>T), located in coding exon 16 of the DICER1 gene, results from a G to T substitution at nucleotide position 2749. This changes the amino acid from a glutamic acid to a stop codon within coding exon 16. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with DICER1-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		6.1
Vest4		0.95
GERP RS		5.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037692; hg19: chr14-95574000; COSMIC: COSV58630227; COSMIC: COSV58630227;