chr14-95096061-C-A

Variant names:

• chr14-95096061-C-A
• rs1555367601
• NM_177438.3:c.4859G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177438.3(DICER1):​c.4859G>T​(p.Ser1620Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1620N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2276859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.4859G>T	p.Ser1620Ile	missense_variant	Exon 23 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.4859G>T	p.Ser1620Ile	missense_variant	Exon 23 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	0.0059	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T;T;T;T;.;.
Eigen	Benign	-0.027
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	.;.;T;.;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.23	T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L
PhyloP100		2.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.60	N;N;N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.050	D;D;D;D;T;D
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.070	B;B;B;B;.;.
Vest4		0.18
MutPred		0.45		Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);.;Loss of disorder (P = 8e-04);
MVP		0.82
MPC		0.60
ClinPred		0.34	T
GERP RS		4.5
Varity_R		0.087
gMVP		0.36
Mutation Taster		=76/24	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: rs1555367601; hg19: chr14-95562398; COSMIC: COSV58623445;