14-95124478-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_177438.3(DICER1):c.1094C>G(p.Pro365Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P365L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.31

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DICER1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.1094C>G	p.Pro365Arg	missense_variant	8/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.1094C>G	p.Pro365Arg	missense_variant	8/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251372 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.1	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.16	N;N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.43	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		1.0	D;D;D;D;.
Vest4		0.79
MutPred		0.43		Gain of methylation at P365 (P = 0.0619);Gain of methylation at P365 (P = 0.0619);Gain of methylation at P365 (P = 0.0619);Gain of methylation at P365 (P = 0.0619);Gain of methylation at P365 (P = 0.0619);
MVP		0.85
MPC		1.4
ClinPred		0.56	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs1060503598; hg19: chr14-95590815;