chr14-95124410-T-C

Variant names:

• chr14-95124410-T-C
• rs1555374717
• NM_177438.3:c.1162A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001395697.1(DICER1):​c.-407A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_001395697.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395697.1. 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.1162A>G	p.Lys388Glu	missense	Exon 8 of 27	NP_803187.1
	DICER1	NM_001395697.1		c.-407A>G		5_prime_UTR_premature_start_codon_gain	Exon 10 of 29	NP_001382626.1
	DICER1	NM_001271282.3		c.1162A>G	p.Lys388Glu	missense	Exon 8 of 27	NP_001258211.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.1162A>G	p.Lys388Glu	missense	Exon 8 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.1162A>G	p.Lys388Glu	missense	Exon 10 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.1162A>G	p.Lys388Glu	missense	Exon 8 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

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	0.90
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D
Sift4G	Benign	0.078	T
Polyphen		0.99	D
Vest4		0.63
MutPred		0.44		Loss of ubiquitination at K388 (P = 0.0255)
MVP		0.64
MPC		1.7
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.71
gMVP		0.81
Mutation Taster		=67/33	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

Other links and lift over

dbSNP: rs1555374717; hg19: chr14-95590747;