rs886037691

Variant names:

• chr14-95107879-C-A
• rs886037691
• NM_177438.3:c.2650+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95107879-C-A
• chr14-95107879-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.2650+1G>T variant in DICER1 occurs within the canonical splice donor (+/- 1) of intron 16 (PVS1). This variant received a total of 2 phenotype points across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PMIDs: 26925222, 26925222, Internal lab contributors) (PS4_Moderate). 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 Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1, PS4_Moderate, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 1; 02/11/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586440/MONDO:0017288/024

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_030621.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.81
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030621.4. 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.2650+1G>T		splice_donor intron	N/A	NP_803187.1
	DICER1	NM_001271282.3		c.2650+1G>T		splice_donor intron	N/A	NP_001258211.1
	DICER1	NM_001291628.2		c.2650+1G>T		splice_donor intron	N/A	NP_001278557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.2650+1G>T		splice_donor intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.2650+1G>T		splice_donor intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.2650+1G>T		splice_donor intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	DICER1-related tumor predisposition (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.8
GERP RS		5.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037691; hg19: chr14-95574216;