rs189119295

chr14-95096101-G-Achr14-95096101-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_177438.3(DICER1):c.4819C>T(p.Arg1607Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1607Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.0860

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DICER1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0585725).
• BP6: Variant 14-95096101-G-A is Benign according to our data. Variant chr14-95096101-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 315102.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000164 (25/152258) while in subpopulation AMR AF= 0.00111 (17/15288). AF 95% confidence interval is 0.000708. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.4819C>T	p.Arg1607Trp	missense_variant	23/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.4819C>T	p.Arg1607Trp	missense_variant	23/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251372 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135844

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000134 AC: 196 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 83 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74456

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28748527) -

DICER1-related tumor predisposition Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.4819C>T (p.R1607W) alteration is located in exon 23 (coding exon 22) of the DICER1 gene. This alteration results from a C to T substitution at nucleotide position 4819, causing the arginine (R) at amino acid position 1607 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;T;T;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.059	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.40	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.017	D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D;D
Polyphen		0.83	P;P;P;P;.;.
Vest4		0.44
MVP		0.64
MPC		0.63
ClinPred		0.058	T
GERP RS		2.0
Varity_R		0.23
gMVP		0.38

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: rs189119295; hg19: chr14-95562438; COSMIC: COSV58619419; COSMIC: COSV58619419;