14-95090659-C-T

Variant names:

• chr14-95090659-C-T
• rs1555366012
• NM_177438.3:c.5608G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_177438.3(DICER1):​c.5608G>A​(p.Ala1870Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. A1870S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36771467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.5608G>A	p.Ala1870Thr	missense_variant	Exon 27 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5608G>A	p.Ala1870Thr	missense_variant	Exon 27 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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T;T;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;.;D;.;D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Benign	-0.54	T
PhyloP100		7.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.86	N;N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.028	D;D;D;D;T
Sift4G	Uncertain	0.058	T;T;T;T;T
Polyphen		0.99	D;D;D;D;.
Vest4		0.46
MutPred		0.37		Gain of phosphorylation at A1870 (P = 0.0485);Gain of phosphorylation at A1870 (P = 0.0485);Gain of phosphorylation at A1870 (P = 0.0485);Gain of phosphorylation at A1870 (P = 0.0485);.;
MVP		0.74
MPC		2.2
ClinPred		0.97	D
GERP RS		6.1
Varity_R		0.31
gMVP		0.58
Mutation Taster		=19/81	disease causing

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: rs1555366012; hg19: chr14-95556996;