rs1555376563

Variant names:

• chr14-95133378-G-C
• rs1555376563
• NM_177438.3:c.81C>G
• DICER1 p.Phe27Leu

Variant summary

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

The NM_001395686.1(DICER1):​c.-194C>G variant causes a 5 prime UTR premature start codon gain 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 (★). The gene DICER1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DICER1 NM_001395686.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66
• 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

Specifications for DICER1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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=0.3687734).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395686.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.81C>G	p.Phe27Leu	missense	Exon 2 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001395686.1		c.-194C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 27	NP_001382615.1
	DICER1	NM_001395688.1		c.-194C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 28	NP_001382617.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.81C>G	p.Phe27Leu	missense	Exon 2 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.81C>G	p.Phe27Leu	missense	Exon 4 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.81C>G	p.Phe27Leu	missense	Exon 2 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.26
Sift	Uncertain	0.023	D
Sift4G	Pathogenic	0.0	D
PromoterAI		0.024	Neutral
Varity_R		0.16
gMVP		0.54
Mutation Taster		=78/22	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555376563;

hg19: chr14-95599715;