14-95103481-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_177438.3(DICER1):c.3915C>G(p.Asn1305Lys) 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 pathogenic 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. N1305H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.181

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DICER1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.3915C>G	p.Asn1305Lys	missense_variant	21/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.3915C>G	p.Asn1305Lys	missense_variant	21/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	10
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;D;D;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.1	L;L;L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D;D;D;D;T;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.26	B;B;B;B;.;.
Vest4		0.87
MutPred		0.80		Gain of ubiquitination at N1305 (P = 0.0185);Gain of ubiquitination at N1305 (P = 0.0185);Gain of ubiquitination at N1305 (P = 0.0185);Gain of ubiquitination at N1305 (P = 0.0185);.;Gain of ubiquitination at N1305 (P = 0.0185);
MVP		0.85
MPC		1.5
ClinPred		0.99	D
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.89

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-95569818;