14-95111337-T-C

Position:

• chr14-95111337-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. BP4 PS2 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.3(DICER1):c.2236A>G variant in DICER1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 746 (p.Arg746Gly). This variant received a total of 1 phenotype point across 1 proband with pleuropulmonary blastoma, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID:26925222). This observation was as a de novo occurrence with constitutional mosaicism (PS2; PMIDs:26925222). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). The computational predictor REVEL gives a score of 0.409, which is below the threshold of 0.5, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PS2, PM2_Supporting, BP4. (Bayesian Points: 5; VCEP specifications version 1.2.0; 08/22/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586443/MONDO:0100216/024

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 4.13

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 Uncertain_significance. Variant got 5 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.2236A>G	p.Arg746Gly	missense_variant	14/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.2236A>G	p.Arg746Gly	missense_variant	14/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota	Nov 10, 2014	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Aug 22, 2023	The NM_177438.3(DICER1):c.2236A>G variant in DICER1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 746 (p.Arg746Gly). This variant received a total of 1 phenotype point across 1 proband with pleuropulmonary blastoma, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 26925222). This observation was as a de novo occurrence with constitutional mosaicism (PS2; PMIDs:26925222). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). The computational predictor REVEL gives a score of 0.409, which is below the threshold of 0.5, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PS2, PM2_Supporting, BP4. (Bayesian Points: 5; VCEP specifications version 1.2.0; 08/22/2023) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Jul 01, 2019

ACMG criteria met: PP3, PP4, BP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;.;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.94	P;P;P;P;.
Vest4		0.81
MutPred		0.41		Loss of catalytic residue at R746 (P = 0.0169);Loss of catalytic residue at R746 (P = 0.0169);Loss of catalytic residue at R746 (P = 0.0169);Loss of catalytic residue at R746 (P = 0.0169);Loss of catalytic residue at R746 (P = 0.0169);
MVP		0.93
MPC		1.6
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.80
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs886037686; hg19: chr14-95577674;