14-95099771-C-CACACACAAAA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_177438.3(DICER1):​c.4206+8_4206+9insTTTTGTGTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000374 in 26,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Likely 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 14-95099771-C-CACACACAAAA is Benign according to our data. Variant chr14-95099771-C-CACACACAAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 543712.Status of the report is criteria_provided_single_submitter, 1 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+8_4206+9insTTTTGTGTGT		splice_region intron	N/A	NP_803187.1
	DICER1	NM_001271282.3		c.4206+8_4206+9insTTTTGTGTGT		splice_region intron	N/A	NP_001258211.1
	DICER1	NM_001291628.2		c.4206+8_4206+9insTTTTGTGTGT		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+9insTTTTGTGTGT		splice_region intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.4206+8_4206+9insTTTTGTGTGT		splice_region intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.4206+8_4206+9insTTTTGTGTGT		splice_region intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.0000374 AC: 1 AN: 26764 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 274868 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 134702

African (AFR) AF: 0.00 AC: 0 AN: 12944

American (AMR) AF: 0.00 AC: 0 AN: 4988

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 14514

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1590

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 213066

Other (OTH) AF: 0.00 AC: 0 AN: 11732

GnomAD4 genome AF: 0.0000374 AC: 1 AN: 26764 Hom.: 0 Cov.: 30 AF XY: 0.0000772 AC XY: 1 AN XY: 12956

African (AFR) AF: 0.0000727 AC: 1 AN: 13764

American (AMR) AF: 0.00 AC: 0 AN: 2098

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: 676

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: 0.00 AC: 0 AN: 7092

Other (OTH) AF: 0.00 AC: 0 AN: 412

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DICER1-related tumor predisposition Benign:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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

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;