14-95099771-C-CACAAAA

Variant names:

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

Variant summary

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

The NM_177438.3(DICER1):​c.4206+8_4206+9insTTTTGT 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000037 (0 hom., cov: 30)
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

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

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 Cov.: 34

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

Not reported in ClinVar

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;