14-95099771-C-CACACACACAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_177438.3(DICER1):​c.4206+8_4206+9insTTGTGTGTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0541 in 26,822 control chromosomes in the GnomAD database, including 53 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.054 (53 hom., cov: 30)
  • Exomes 𝑓: 0.0023 (20 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 14-95099771-C-CACACACACAA is Benign according to our data. Variant chr14-95099771-C-CACACACACAA is described in ClinVar as Benign. ClinVar VariationId is 220997.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.4206+8_4206+9insTTGTGTGTGT		splice_region_variant, intron_variant	Intron 22 of 26	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.4206+8_4206+9insTTGTGTGTGT		splice_region_variant, intron_variant	Intron 22 of 26	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes AF: 0.0541 AC: 1448 AN: 26742 Hom.: 53 Cov.: 30

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000564

Gnomad OTH AF: 0.0340

GnomAD2 exomes AF: 0.00167 AC: 285 AN: 170614 AF XY: 0.00118

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000386

Gnomad OTH exome AF: 0.00118

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00230 AC: 632 AN: 274658 Hom.: 20 Cov.: 34 AF XY: 0.00186 AC XY: 251 AN XY: 134616

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

African (AFR) AF: 0.0397 AC: 507 AN: 12770

American (AMR) AF: 0.00642 AC: 32 AN: 4982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4588

East Asian (EAS) AF: 0.00 AC: 0 AN: 2420

South Asian (SAS) AF: 0.000276 AC: 4 AN: 14510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9026

Middle Eastern (MID) AF: 0.00252 AC: 4 AN: 1588

European-Non Finnish (NFE) AF: 0.0000422 AC: 9 AN: 213064

Other (OTH) AF: 0.00649 AC: 76 AN: 11710

⚠️ 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: 0.0541 AC: 1450 AN: 26822 Hom.: 53 Cov.: 30 AF XY: 0.0517 AC XY: 674 AN XY: 13034

African (AFR) AF: 0.101 AC: 1394 AN: 13814

American (AMR) AF: 0.0181 AC: 38 AN: 2094

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

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

South Asian (SAS) AF: 0.00 AC: 0 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: 0.000564 AC: 4 AN: 7088

Other (OTH) AF: 0.0333 AC: 14 AN: 420

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

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Computational scores

Source: dbNSFP v4.3

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;