chr14-95099771-C-CAA

Variant names:

• chr14-95099771-C-CAA
• rs1555368535
• NM_177438.3:c.4206+7_4206+8dupTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_177438.3(DICER1):​c.4206+7_4206+8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 26,818 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene DICER1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.048 (29 hom., cov: 30)
  • Exomes 𝑓: 0.018 (101 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.425
• Publications: 0 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

Specifications for DICER1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 14-95099771-C-CAA is Benign according to our data. Variant chr14-95099771-C-CAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221129.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.4206+7_4206+8dupTT		splice_region intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+7_4206+8dupTT		splice_region intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+7_4206+8dupTT		splice_region intron	N/A	NP_001278557.1	Q9UPY3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4206+8_4206+9insTT		splice_region intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+8_4206+9insTT		splice_region intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+8_4206+9insTT		splice_region intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 1289 AN: 26738 Hom.: 29 Cov.: 30

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0410

Gnomad EAS AF: 0.0155

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.00540

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0461

GnomAD2 exomes AF: 0.00964 AC: 1645 AN: 170614 AF XY: 0.00887

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00414

Gnomad NFE exome AF: 0.00623

Gnomad OTH exome AF: 0.0115

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0183 AC: 4990 AN: 272402 Hom.: 101 Cov.: 34 AF XY: 0.0185 AC XY: 2470 AN XY: 133590

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

African (AFR) AF: 0.0546 AC: 693 AN: 12700

American (AMR) AF: 0.0487 AC: 240 AN: 4924

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 123 AN: 4516

East Asian (EAS) AF: 0.0183 AC: 44 AN: 2402

South Asian (SAS) AF: 0.0266 AC: 381 AN: 14336

European-Finnish (FIN) AF: 0.00322 AC: 29 AN: 9006

Middle Eastern (MID) AF: 0.0375 AC: 59 AN: 1574

European-Non Finnish (NFE) AF: 0.0148 AC: 3128 AN: 211356

Other (OTH) AF: 0.0253 AC: 293 AN: 11588

⚠️ 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: 0.0484 AC: 1299 AN: 26818 Hom.: 29 Cov.: 30 AF XY: 0.0445 AC XY: 580 AN XY: 13022

African (AFR) AF: 0.0624 AC: 862 AN: 13822

American (AMR) AF: 0.0344 AC: 72 AN: 2092

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 22 AN: 536

East Asian (EAS) AF: 0.0155 AC: 3 AN: 194

South Asian (SAS) AF: 0.0367 AC: 25 AN: 682

European-Finnish (FIN) AF: 0.00540 AC: 10 AN: 1852

Middle Eastern (MID) AF: 0.100 AC: 7 AN: 70

European-Non Finnish (NFE) AF: 0.0394 AC: 279 AN: 7080

Other (OTH) AF: 0.0452 AC: 19 AN: 420

Alfa AF: 0.00806 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	2	DICER1-related tumor predisposition (2)
-	-	1	Pleuropulmonary blastoma (1)

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: rs1555368535; hg19: chr14-95566108; COSMIC: COSV100601699; COSMIC: COSV100601699;