14-95099780-C-A

Position:

• chr14-95099780-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000343455.8(DICER1):​c.4206G>T​(p.Met1402Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1402K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 ENST00000343455.8 missense, splice_region
• Scores: Splicing: ADA: 0.8186
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DICER1. . Gene score misZ 4.2261 (greater than the threshold 3.09). Trascript score misZ 6.1353 (greater than threshold 3.09). GenCC has associacion of gene with goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome, DICER1-related tumor predisposition, DICER1 syndrome, pleuropulmonary blastoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13652647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.4206G>T	p.Met1402Ile	missense_variant, splice_region_variant	22/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.4206G>T	p.Met1402Ile	missense_variant, splice_region_variant	22/27	1	NM_177438.3	ENSP00000343745	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.91e-7 AC: 1 AN: 1448142 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 720936

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2018

The p.M1402I variant (also known as c.4206G>TI), located in coding exon 21 of the DICER1 gene, results from a G to T substitution at nucleotide position 4206. The amino acid change results in methionine to isoleucine at codon 1402, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP splice site prediction tool, this alteration is not predicted to have a deleterious effect on this splice donor site. Using the ESEfinder and the Human Splicing Finder (HSF) splice site prediction tool this alteration is predicted weaken the native splice donor site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;T;T;T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	.;.;T;.;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	N;N;N;N;.;N
MutationTaster	Benign	0.79	D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.060	N;N;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.35	T;T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;.
Vest4		0.15
MutPred		0.38		Loss of disorder (P = 0.0833);Loss of disorder (P = 0.0833);Loss of disorder (P = 0.0833);Loss of disorder (P = 0.0833);.;Loss of disorder (P = 0.0833);
MVP		0.77
MPC		0.55
ClinPred		0.48	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.15		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: rs866519895; hg19: chr14-95566117;