rs886037729

chr14-95091265-T-Achr14-95091265-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_177438.3(DICER1):c.5465A>T(p.Asp1822Val) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1822G) has been classified as Likely pathogenic.

• 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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 16) in uniprot entity DICER_HUMAN there are 28 pathogenic changes around while only 0 benign (100%) in NM_177438.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-95091265-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429125.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, DICER1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 14-95091265-T-A is Pathogenic according to our data. Variant chr14-95091265-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254350.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-95091265-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.5465A>T	p.Asp1822Val	missense_variant	25/27	1	NM_177438.3	P1

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

Likely pathogenic, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	May 18, 2022	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 v2.1.1 and v.3.1.1 (PM2_Supporting). In vitro cleavage assay in HEK293 cells 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). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for DICER1 syndrome 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; 02/11/2022) -
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 -

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
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;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
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;