14-95090657-A-C

Variant names:

• chr14-95090657-A-C
• rs1060504961
• ENST00000541352.5:c.5447T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The ENST00000541352.5(DICER1):​c.5447T>G​(p.Leu1816Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1816P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DICER1 ENST00000541352.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.48
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3462528).
• BP6: Variant 14-95090657-A-C is Benign according to our data. Variant chr14-95090657-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 417057.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000541352.5. 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.5610T>G	p.Ala1870Ala	synonymous	Exon 27 of 27	NP_803187.1
	DICER1	NM_001195573.1		c.5447T>G	p.Leu1816Arg	missense	Exon 25 of 25	NP_001182502.1
	DICER1	NM_001271282.3		c.5610T>G	p.Ala1870Ala	synonymous	Exon 27 of 27	NP_001258211.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000541352.5	TSL:1	c.5447T>G	p.Leu1816Arg	missense	Exon 25 of 25	ENSP00000444719.1
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.5610T>G	p.Ala1870Ala	synonymous	Exon 27 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.5610T>G	p.Ala1870Ala	synonymous	Exon 29 of 29	ENSP00000376783.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DICER1-related tumor predisposition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	3.0
DANN	Benign	0.85
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.90	T
PhyloP100		-1.5
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Vest4		0.15
MutPred		0.90		Gain of MoRF binding (P = 0.0093)
MVP		0.59
ClinPred		0.033	T
GERP RS		-11
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1060504961; hg19: chr14-95556994;