14-95099771-C-CACACAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_177438.3(DICER1):​c.4206+8_4206+9insTTGTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 26,840 control chromosomes in the GnomAD database, including 10 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (10 hom., cov: 30)
  • Exomes 𝑓: 0.0016 (17 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-CACACAA is Benign according to our data. Variant chr14-95099771-C-CACACAA is described in ClinVar as Benign. ClinVar VariationId is 242102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0159 (428/26840) while in subpopulation AFR AF = 0.0274 (379/13832). AF 95% confidence interval is 0.0251. There are 10 homozygotes in GnomAd4. There are 212 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 428 AD,Unknown gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 425 AN: 26760 Hom.: 10 Cov.: 30

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00296

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0286

Gnomad NFE AF: 0.000423

Gnomad OTH AF: 0.00971

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00158 AC: 435 AN: 274656 Hom.: 17 Cov.: 34 AF XY: 0.00142 AC XY: 191 AN XY: 134606

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

African (AFR) AF: 0.0217 AC: 279 AN: 12840

American (AMR) AF: 0.00805 AC: 40 AN: 4968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4586

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

South Asian (SAS) AF: 0.000413 AC: 6 AN: 14514

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

Middle Eastern (MID) AF: 0.00189 AC: 3 AN: 1590

European-Non Finnish (NFE) AF: 0.000258 AC: 55 AN: 213002

Other (OTH) AF: 0.00444 AC: 52 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: 0.0159 AC: 428 AN: 26840 Hom.: 10 Cov.: 30 AF XY: 0.0163 AC XY: 212 AN XY: 13038

African (AFR) AF: 0.0274 AC: 379 AN: 13832

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: 0.00292 AC: 2 AN: 684

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

Middle Eastern (MID) AF: 0.0286 AC: 2 AN: 70

European-Non Finnish (NFE) AF: 0.000423 AC: 3 AN: 7088

Other (OTH) AF: 0.00952 AC: 4 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

Jul 09, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DICER1-related tumor predisposition Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.42

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;