rs1555371562

Positions:

• chr14-95111311-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3 PP1 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.2256+6T>A variant in DICER1 is an intronic variant which located in intron 14. This variant received a total of 1 phenotype points across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Invitae, Ambry). The variant has been reported to segregate with DICER1 syndrome in 4 affected meioses from 1 family (PP1; Invitae, Ambry, NCI). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). 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: PS4_Supporting, PP1, PM2_Supporting, PP3. (Bayesian Points: 4; VCEP specifications version 1.1.0; 2/28/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658798256/MONDO:0017288/024

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_001395698.1 missense
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 8.81

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.2256+6T>A		splice_region_variant, intron_variant		ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.2256+6T>A		splice_region_variant, intron_variant		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: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Mar 01, 2023	The NM_177438.2:c.2256+6T>A variant in DICER1 is an intronic variant which located in intron 14. This variant received a total of 1 phenotype points across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Invitae, Ambry). The variant has been reported to segregate with DICER1 syndrome in 4 affected meioses from 1 family (PP1; Invitae, Ambry, NCI). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). 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: PS4_Supporting, PP1, PM2_Supporting, PP3. (Bayesian Points: 4; VCEP specifications version 1.1.0; 2/28/2023) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2017	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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with DICER1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 14 of the DICER1 gene. It does not directly change the encoded amino acid sequence of the DICER1 protein, but it affects a nucleotide within the consensus splice site of the intron. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: 41
DS_DL_spliceai		0.85		Position offset: 6

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555371562; hg19: chr14-95577648;