14-95124604-C-T

Variant names:

• chr14-95124604-C-T
• rs906299601
• NM_177438.3:c.968G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_177438.3(DICER1):​c.968G>A​(p.Gly323Glu) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G323R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.35
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

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.968G>A	p.Gly323Glu	missense	Exon 8 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.968G>A	p.Gly323Glu	missense	Exon 8 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.968G>A	p.Gly323Glu	missense	Exon 8 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.968G>A	p.Gly323Glu	missense	Exon 8 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.968G>A	p.Gly323Glu	missense	Exon 10 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.968G>A	p.Gly323Glu	missense	Exon 8 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:1

Jan 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DICER1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 323 of the DICER1 protein (p.Gly323Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid.

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G323E variant (also known as c.968G>A), located in coding exon 7 of the DICER1 gene, results from a G to A substitution at nucleotide position 968. The glycine at codon 323 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.60	N
REVEL	Uncertain	0.37
Sift	Benign	0.27	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.49		Gain of sheet (P = 0.0221)
MVP		0.85
MPC		1.6
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.60
gMVP		0.79
Mutation Taster		=41/59	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: rs906299601; hg19: chr14-95590941;