rs544623004

chr14-95113099-G-A

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.2033C>T(p.Ser678Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S678A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 9.05

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=0.06353626).
• BP6: Variant 14-95113099-G-A is Benign according to our data. Variant chr14-95113099-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242055.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000788 (12/152266) while in subpopulation EAS AF= 0.00231 (12/5192). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.2033C>T	p.Ser678Phe	missense_variant	12/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.2033C>T	p.Ser678Phe	missense_variant	12/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251360 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000903 AC: 132 AN: 1461408 Hom.: 0 Cov.: 31 AF XY: 0.0000894 AC XY: 65 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00330

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74446

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 15, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 23, 2021	- -

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 12, 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 17, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 27, 2023

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: 31911633) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;T;T;.
Eigen	Benign	-0.0077
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.064	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.057	T;T;T;T;T
Sift4G	Benign	0.073	T;T;T;T;T
Polyphen		0.025	B;B;B;B;.
Vest4		0.49
MutPred		0.59		Loss of phosphorylation at S678 (P = 0.0435);Loss of phosphorylation at S678 (P = 0.0435);Loss of phosphorylation at S678 (P = 0.0435);Loss of phosphorylation at S678 (P = 0.0435);Loss of phosphorylation at S678 (P = 0.0435);
MVP		0.58
MPC		0.91
ClinPred		0.21	T
GERP RS		4.9
Varity_R		0.48
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs544623004; hg19: chr14-95579436; COSMIC: COSV58621788; COSMIC: COSV58621788;