NM_177438.3:c.4206+8_4206+9insTTGT

Variant names:

• chr14-95099771-C-CACAA
• rs763704682
• NM_177438.3:c.4206+8_4206+9insTTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_177438.3(DICER1):​c.4206+8_4206+9insTTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 26,826 control chromosomes in the GnomAD database, including 52 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (52 hom., cov: 30)
  • Exomes 𝑓: 0.0045 (44 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.425
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 14-95099771-C-CACAA is Benign according to our data. Variant chr14-95099771-C-CACAA is described in ClinVar as Benign. ClinVar VariationId is 221051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

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+8_4206+9insTTGT		splice_region intron	N/A	NP_803187.1
	DICER1	NM_001271282.3		c.4206+8_4206+9insTTGT		splice_region intron	N/A	NP_001258211.1
	DICER1	NM_001291628.2		c.4206+8_4206+9insTTGT		splice_region 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+8_4206+9insTTGT		splice_region intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.4206+8_4206+9insTTGT		splice_region intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.4206+8_4206+9insTTGT		splice_region intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 1413 AN: 26746 Hom.: 54 Cov.: 30

Gnomad AFR AF: 0.0898

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00296

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.0607

GnomAD2 exomes AF: 0.00329 AC: 561 AN: 170614 AF XY: 0.00241

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.000713

Gnomad EAS exome AF: 0.0000787

Gnomad FIN exome AF: 0.0000797

Gnomad NFE exome AF: 0.000463

Gnomad OTH exome AF: 0.00118

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00449 AC: 1231 AN: 274410 Hom.: 44 Cov.: 34 AF XY: 0.00432 AC XY: 581 AN XY: 134510

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

African (AFR) AF: 0.0589 AC: 750 AN: 12742

American (AMR) AF: 0.0185 AC: 92 AN: 4964

Ashkenazi Jewish (ASJ) AF: 0.000654 AC: 3 AN: 4586

East Asian (EAS) AF: 0.000413 AC: 1 AN: 2420

South Asian (SAS) AF: 0.00310 AC: 45 AN: 14506

European-Finnish (FIN) AF: 0.000554 AC: 5 AN: 9026

Middle Eastern (MID) AF: 0.00694 AC: 11 AN: 1586

European-Non Finnish (NFE) AF: 0.000935 AC: 199 AN: 212896

Other (OTH) AF: 0.0107 AC: 125 AN: 11684

⚠️ 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 AF: 0.0528 AC: 1416 AN: 26826 Hom.: 52 Cov.: 30 AF XY: 0.0491 AC XY: 640 AN XY: 13032

African (AFR) AF: 0.0895 AC: 1237 AN: 13820

American (AMR) AF: 0.0612 AC: 128 AN: 2092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 536

East Asian (EAS) AF: 0.00 AC: 0 AN: 194

South Asian (SAS) AF: 0.00292 AC: 2 AN: 684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 70

European-Non Finnish (NFE) AF: 0.00339 AC: 24 AN: 7088

Other (OTH) AF: 0.0595 AC: 25 AN: 420

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

DICER1-related tumor predisposition Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.42
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: rs763704682; hg19: chr14-95566108;