14-95133434-G-C

Variant names:

• chr14-95133434-G-C
• rs1482976224
• NM_177438.3:c.25C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_177438.3(DICER1):​c.25C>G​(p.Leu9Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. L9F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.74
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36409396).

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.25C>G	p.Leu9Val	missense	Exon 2 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.25C>G	p.Leu9Val	missense	Exon 2 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.25C>G	p.Leu9Val	missense	Exon 2 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.25C>G	p.Leu9Val	missense	Exon 2 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.25C>G	p.Leu9Val	missense	Exon 4 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.25C>G	p.Leu9Val	missense	Exon 2 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L9V variant (also known as c.25C>G), located in coding exon 1 of the DICER1 gene, results from a C to G substitution at nucleotide position 25. The leucine at codon 9 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.0036	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.55	N
PhyloP100		6.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.24
Sift	Uncertain	0.016	D
Sift4G	Benign	0.38	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.12		Loss of disorder (P = 0.0676)
MVP		0.67
MPC		0.64
ClinPred		0.89	D
GERP RS		5.4
PromoterAI		0.080	Neutral
Varity_R		0.13
gMVP		0.46
Mutation Taster		=48/52	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: rs1482976224; hg19: chr14-95599771;