chr14-95099766-ACACAC-A

Variant names:

• chr14-95099766-ACACAC-A
• rs745445238
• NM_177438.3:c.4206+9_4206+13delGTGTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_177438.3(DICER1):​c.4206+9_4206+13delGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 0)
  • Exomes 𝑓: 0.12 (776 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.918
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• DICER1-related tumor predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pleuropulmonary blastoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• DICER1 syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 14-95099766-ACACAC-A is Benign according to our data. Variant chr14-95099766-ACACAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 429146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.4206+9_4206+13delGTGTG		intron	N/A	NP_803187.1
	DICER1	NM_001271282.3		c.4206+9_4206+13delGTGTG		intron	N/A	NP_001258211.1
	DICER1	NM_001291628.2		c.4206+9_4206+13delGTGTG		intron	N/A	NP_001278557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4206+9_4206+13delGTGTG		intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.4206+9_4206+13delGTGTG		intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.4206+9_4206+13delGTGTG		intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 1876 AN: 130922 Hom.: 26 Cov.: 0

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.0181

Gnomad AMR AF: 0.00951

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.0306

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0105

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.0132

GnomAD2 exomes AF: 0.0351 AC: 7362 AN: 209476 AF XY: 0.0360

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.0296

Gnomad ASJ exome AF: 0.0418

Gnomad EAS exome AF: 0.0239

Gnomad FIN exome AF: 0.0237

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0341

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.123 AC: 147255 AN: 1194126 Hom.: 776 AF XY: 0.125 AC XY: 73949 AN XY: 593282

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0773 AC: 2059 AN: 26638

American (AMR) AF: 0.127 AC: 4345 AN: 34330

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 2928 AN: 21570

East Asian (EAS) AF: 0.110 AC: 2701 AN: 24536

South Asian (SAS) AF: 0.140 AC: 9438 AN: 67388

European-Finnish (FIN) AF: 0.109 AC: 4405 AN: 40330

Middle Eastern (MID) AF: 0.0880 AC: 409 AN: 4646

European-Non Finnish (NFE) AF: 0.124 AC: 114978 AN: 925166

Other (OTH) AF: 0.121 AC: 5992 AN: 49522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0143 AC: 1877 AN: 131010 Hom.: 26 Cov.: 0 AF XY: 0.0149 AC XY: 943 AN XY: 63440

African (AFR) AF: 0.0330 AC: 1122 AN: 34030

American (AMR) AF: 0.00949 AC: 122 AN: 12858

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 32 AN: 3098

East Asian (EAS) AF: 0.0102 AC: 36 AN: 3538

South Asian (SAS) AF: 0.0304 AC: 121 AN: 3984

European-Finnish (FIN) AF: 0.0110 AC: 97 AN: 8794

Middle Eastern (MID) AF: 0.0113 AC: 3 AN: 266

European-Non Finnish (NFE) AF: 0.00492 AC: 304 AN: 61726

Other (OTH) AF: 0.0131 AC: 24 AN: 1830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Benign:2

Jun 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 19, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria.

Hereditary cancer-predisposing syndrome Benign:1

Nov 02, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.92
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs745445238; hg19: chr14-95566103;