rs387906934

Variant names:

• chr14-95108014-G-A
• rs387906934
• NM_177438.3:c.2516C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95108014-G-A
• chr14-95108014-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3_Supporting PP1_Moderate PP4 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.2516C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 839 (p.Ser839Phe). This variant received a total of 1 phenotype point across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs: 3799599, 21205968; Internal Contributors: Guy's and St Thomas’ NHS Foundation Trust). All reported phenotypes to date have been thyroid phenotypes (multi-nodular goiter and thyroid cancer, including pediatric). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMIDs: 27459524, 26033159). The variant has been reported to segregate with multi-nodular goiter in 20 affected family members from 1 family (PP1_Moderate; PMIDs: 2120596). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Ser839Phe showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; Wu, McGill 2018; Torrez, University of Michigan 2023, PMID:37333613). The computational predictor REVEL gives a score of 0.519, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PP1_Moderate, PM2_Supporting, PS3_Supporting. (Bayesian Points: 6; VCEP specifications version 1.2.0; 01/09/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA129336/MONDO:0100216/024

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 3.23
• Publications: 11 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.2516C>T	p.Ser839Phe	missense	Exon 16 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.2516C>T	p.Ser839Phe	missense	Exon 16 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.2516C>T	p.Ser839Phe	missense	Exon 16 of 27	NP_001278557.1	Q9UPY3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.2516C>T	p.Ser839Phe	missense	Exon 16 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.2516C>T	p.Ser839Phe	missense	Exon 18 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.2516C>T	p.Ser839Phe	missense	Exon 16 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	DICER1-related tumor predisposition (3)
1	-	-	Euthyroid goiter (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.028	D
Polyphen		0.83	P
Vest4		0.75
MutPred		0.60		Loss of catalytic residue at S839 (P = 0.0447)
MVP		0.95
MPC		1.0
ClinPred		0.86	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.74
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs387906934; hg19: chr14-95574351;