rs886037729

Positions:

• chr14-95091265-T-A
• chr14-95091265-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PM1_Supporting PS4_Moderate PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5465A>T variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1822 (p.Asp1822Val). This variant received a total of 3 phenotype points across 3 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PMIDs: 26925222, 21266384) (PS4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Asp1822Val showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (Wu 2018, McGill University) (PS3_Supporting). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID:31342592) (PM1_Supporting). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.954) (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Moderate, PM1_Supporting, PM2_supporting, PS3_Supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1.3.0; 08/27/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586400/MONDO:0017288/024

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.50

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.5465A>T	p.Asp1822Val	missense_variant	25/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5465A>T	p.Asp1822Val	missense_variant	25/27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota	Nov 10, 2014	- -
Likely pathogenic, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: PS3, PM1, PM2, PP4 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Aug 27, 2024	The NM_177438.2:c.5465A>T variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1822 (p.Asp1822Val). This variant received a total of 3 phenotype points across 3 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PMIDs: 26925222, 21266384) (PS4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Asp1822Val showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (Wu 2018, McGill University) (PS3_Supporting). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID: 31342592) (PM1_Supporting). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.954) (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Moderate, PM1_Supporting, PM2_supporting, PS3_Supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1.3.0; 08/27/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;.;D;.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;H;H;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.3	D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.99
MutPred		0.87		Gain of catalytic residue at S1826 (P = 0.071);Gain of catalytic residue at S1826 (P = 0.071);Gain of catalytic residue at S1826 (P = 0.071);Gain of catalytic residue at S1826 (P = 0.071);.;
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886037729; hg19: chr14-95557602;