14-95091265-T-C

Variant names:

• chr14-95091265-T-C
• rs886037729
• NM_177438.3:c.5465A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PP1 PM2_Supporting PM1_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_177438.3:c.5465A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1822 (p.Asp1822Gly). This variant received a total of 2 phenotype points across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PS4_Moderate; Ambry). The variant has been reported to segregate with Sertoli Leydig cell tumors, PPB, and lung cysts in 4 meioses from 2 families (PP1; Ambry). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.956) (PP3). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID:31342592). 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, PP1, PM2_Supporting, PP3, PM1_Supporting. (Bayesian Points: 6; VCEP specifications version 1.3.0; 10/22/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA390864594/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
• Publications: 9 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: Likely_pathogenic. The variant received 6 ACMG points.

• 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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.5465A>G	p.Asp1822Gly	missense	Exon 25 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.5465A>G	p.Asp1822Gly	missense	Exon 25 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.5465A>G	p.Asp1822Gly	missense	Exon 25 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.5465A>G	p.Asp1822Gly	missense	Exon 25 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.5465A>G	p.Asp1822Gly	missense	Exon 27 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.5465A>G	p.Asp1822Gly	missense	Exon 25 of 27	ENSP00000435681.1

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:2

Oct 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1822 of the DICER1 protein (p.Asp1822Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of DICER1-related conditions (external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 429125). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DICER1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Asp1822 amino acid residue in DICER1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21266384, 26925222). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Oct 22, 2024

ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_177438.3:c.5465A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1822 (p.Asp1822Gly). This variant received a total of 2 phenotype points across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PS4_Moderate; Ambry). The variant has been reported to segregate with Sertoli Leydig cell tumors, PPB, and lung cysts in 4 meioses from 2 families (PP1; Ambry). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.956) (PP3). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). 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, PP1, PM2_Supporting, PP3, PM1_Supporting. (Bayesian Points: 6; VCEP specifications version 1.3.0; 10/22/2024)

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 19, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1822G variant (also known as c.5465A>G), located in coding exon 24 of the DICER1 gene, results from an A to G substitution at nucleotide position 5465. The aspartic acid at codon 1822 is replaced by glycine, an amino acid with similar properties. This alteration has been observed in individuals with a personal and family history that is consistent with DICER1-related disease (Ambry internal data). This alteration has also been observed to co-segregate with DICER1-related disease with several families (Ambry internal data). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical function (de Kock L et al. Hum Mutat, 2019 Nov;40:1939-1953). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.98
MutPred		0.86		Loss of stability (P = 0.0897)
MVP		0.96
MPC		2.7
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.92
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886037729; hg19: chr14-95557602; COSMIC: COSV58628200;