14-95115670-T-C

Position:

chr14-95115670-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.1904A>G variant in DICER1 is a missense variant predicted to cause substitution of Aspartic Acid by Serine at amino acid 635 (p.Asp635Ser). This variant received 0 phenotype points across 16 probands, including 3 unrelated females without tumors through age 50 (GTRs: 61756, 500031, PMID:33718253) (PS4 and BS2 are not met). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00003 (1/30526 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.398, which is below the threshold of 0.5; however, the splice site predictors MaxEntScan and SpliceAI indicate creation of a new donor splice site (BP4 and PP3 not met). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: No criteria. (Bayesian Points: 0; VCEP specifications version 1.1.0; 10/25/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7331374/MONDO:0017288/024

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 7.81

Variant links:

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 links:

DICER1 (HGNC:):

DICER1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.1904A>G	p.Asn635Ser	missense_variant	11/27	ENST00000343455.8	NP_803187.1	Q9UPY3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.1904A>G	p.Asn635Ser	missense_variant	11/27	1	NM_177438.3	ENSP00000343745.3		Q9UPY3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251466

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727240

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 635 of the DICER1 protein (p.Asn635Ser). This variant is present in population databases (rs765551529, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 479636). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DICER1 protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Oct 25, 2022	The NM_177438.2:c.1904A>G variant in DICER1 is a missense variant predicted to cause substitution of Aspartic Acid by Serine at amino acid 635 (p.Asp635Ser). This variant received 0 phenotype points across 16 probands, including 3 unrelated females without tumors through age 50 (GTRs: 61756, 500031, PMID: 33718253) (PS4 and BS2 are not met). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00003 (1/30526 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.398, which is below the threshold of 0.5; however, the splice site predictors MaxEntScan and SpliceAI indicate creation of a new donor splice site (BP4 and PP3 not met). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: No criteria. (Bayesian Points: 0; VCEP specifications version 1.1.0; 10/25/2022). -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Hereditary Cancer Group, L’Institut d'Investigació Biomèdica de Bellvitge	Dec 19, 2024	PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 21, 2023	The p.N635S variant (also known as c.1904A>G), located in coding exon 10 of the DICER1 gene, results from an A to G substitution at nucleotide position 1904. The asparagine at codon 635 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in the germline of an individual with reported papillary thyroid cancer from The Cancer Genome Atlas (TCGA) research network (Canberk S et al. Eur Thyroid J 2021 Feb;9(6):296-303). This amino acid position is highly 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

Pathogenic

0.76

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D;D;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;.;D;.;D

M_CAP

Benign

0.056

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.7

M;M;M;M;M

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.6

D;D;D;D;D

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.81

P;P;P;P;.

Vest4

0.92

MutPred

0.67

Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);

MVP

0.78

MPC

1.2

ClinPred

0.98

GERP RS

4.9

Varity_R

0.89

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.84

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over