14-95111326-G-T

Position:

• chr14-95111326-G-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.2247C>A​(p.Tyr749Ter) 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. Y749Y) 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:4
• Conservation: PhyloP100: 4.20

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 14-95111326-G-T is Pathogenic according to our data. Variant chr14-95111326-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 254308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95111326-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.2247C>A	p.Tyr749Ter	stop_gained	14/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.2247C>A	p.Tyr749Ter	stop_gained	14/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:2

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

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 17, 2017

This variant is denoted DICER1 c.2247C>A at the cDNA level and p.Tyr749Ter (Y749X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. DICER1 Tyr749Ter segregated with disease in a large family with DICER1-Pleuropulmonary Blastoma Familial Tumor Predisposition Syndrome, and lymphoblasts from carriers of this variant showed reduction of the variant mRNA (Hill 2009). DICER1 Tyr749Ter has also been reported in at least two other individuals with personal and family histories of DICER1-related tumors (Doros 2012, Brenneman 2015). This variant is considered pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2013

​The p.Y749X pathogenic mutation (also known as c.2247C>A), located in coding exon 13 of the DICER1 gene, results from a C to A substitution at nucleotide position 2247. This changes the amino acid from a tyrosine to a stop codon within coding exon 13. In one study, this mutation was observed in a family with pleuropulmonary blastoma, with marked reduction in mRNA containing this mutation in lymphoblasts of individuals with this mutation. In this paper this mutation is known as p.Y739X (Hill DA et al. Science. 2009. Aug 21; 325 (5943): 965. Supporting Online Material). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.95
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs886037689; hg19: chr14-95577663;