rs1184678913

chr14-95094004-C-Achr14-95094004-C-Gchr14-95094004-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_177438.3(DICER1):c.5248G>T(p.Val1750Leu) 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 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. V1750I) 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: 7.50

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain RNase III 2 (size 158) in uniprot entity DICER_HUMAN there are 51 pathogenic changes around while only 4 benign (93%) in NM_177438.3
• 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, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.5248G>T	p.Val1750Leu	missense_variant	24/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.5248G>T	p.Val1750Leu	missense_variant	24/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D;D;D;D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	2.0	M;M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0070	D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;.;.
Vest4		0.80
MutPred		0.51		Loss of stability (P = 0.2803);Loss of stability (P = 0.2803);Loss of stability (P = 0.2803);Loss of stability (P = 0.2803);.;Loss of stability (P = 0.2803);
MVP		0.92
MPC		2.4
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.84
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr14-95560341;