rs1555366154

Variant names:

• chr14-95091209-G-A
• rs1555366154
• NM_177438.3:c.5521C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. BP7 PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5521C>T (p.Leu1841=) variant is a synonymous (silent) variant that is not predicted by MaxEntScan or SpliceAI to impact splicing (BP4, BP7). This variant is absent from gnomAD v2.1.1 and v.3.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for DICER1 syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4, BP7, PM2_Supporting. (Bayesian Points: -1; VCEP specifications version 1; 02/11/22) LINK:https://erepo.genome.network/evrepo/ui/classification/CA487843671/MONDO:0017288/024

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DICER1 NM_177438.3 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: 3.50
• 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: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.5521C>T	p.Leu1841Leu	synonymous	Exon 25 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.5521C>T	p.Leu1841Leu	synonymous	Exon 25 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.5521C>T	p.Leu1841Leu	synonymous	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.5521C>T	p.Leu1841Leu	synonymous	Exon 25 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.5521C>T	p.Leu1841Leu	synonymous	Exon 27 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.5521C>T	p.Leu1841Leu	synonymous	Exon 25 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111982

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	DICER1-related tumor predisposition (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.5
DANN	Benign	0.33
PhyloP100		3.5

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: rs1555366154; hg19: chr14-95557546;