chr14-95111311-A-T

Variant names:

• chr14-95111311-A-T
• rs1555371562
• NM_177438.3:c.2256+6T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3 PP1 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.2256+6T>A variant in DICER1 is an intronic variant which located in intron 14. This variant received a total of 1 phenotype points across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Invitae, Ambry). The variant has been reported to segregate with PPB in 3 affected family members (4 meioses) from 1 family (PP1; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The splice site predictor SpliceAI indicates that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP1, PM2_Supporting, PP3. (Bayesian Points: 4; VCEP specifications version 1.3.0; 02/25/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658798256/MONDO:0100216/024

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_001395698.1 missense
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 8.81
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395698.1. 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.2256+6T>A		splice_region intron	N/A	NP_803187.1
	DICER1	NM_001395698.1		c.1857T>A	p.Ser619Arg	missense	Exon 13 of 13	NP_001382627.1
	DICER1	NM_001271282.3		c.2256+6T>A		splice_region intron	N/A	NP_001258211.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.2256+6T>A		splice_region intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.2256+6T>A		splice_region intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.2256+6T>A		splice_region intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	DICER1-related tumor predisposition (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.98
PhyloP100		8.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: 41
DS_DL_spliceai		0.85		Position offset: 6

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

Other links and lift over

dbSNP: rs1555371562; hg19: chr14-95577648;