rs878855259

Variant names:

• chr14-95103736-C-A
• rs878855259
• NM_177438.3:c.3660G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95103736-C-A
• chr14-95103736-C-T

Variant summary

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

The NM_177438.3(DICER1):​c.3660G>T​(p.Gln1220His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1220R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.14
• 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=0.33834702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.3660G>T	p.Gln1220His	missense_variant	Exon 21 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.3660G>T	p.Gln1220His	missense_variant	Exon 21 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1

Nov 27, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

May 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;T;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;.;T;.;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.8	L;L;L;L;.;L
PhyloP100		7.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.030	N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D;D;D;D;D;D
Sift4G	Uncertain	0.048	D;D;D;D;T;D
Polyphen		0.85	P;P;P;P;.;.
Vest4		0.46
MutPred		0.35		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;Loss of helix (P = 0.0237);
MVP		0.88
MPC		0.83
ClinPred		0.78	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.59
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs878855259; hg19: chr14-95570073;