chr14-95099771-C-A

Variant names:

• chr14-95099771-C-A
• rs1778057
• NM_177438.3:c.4206+9G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_177438.3(DICER1):​c.4206+9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene DICER1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.26 (240 hom., cov: 0)
  • Exomes 𝑓: 0.18 (1846 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.327
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-95099771-C-A is Benign according to our data. Variant chr14-95099771-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 315105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.427 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+9G>T		intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+9G>T		intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+9G>T		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+9G>T		intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+9G>T		intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+9G>T		intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 7044 AN: 26688 Hom.: 241 Cov.: 0

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.286

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.467 AC: 79663 AN: 170614 AF XY: 0.462

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.418

Gnomad EAS exome AF: 0.485

Gnomad FIN exome AF: 0.471

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.471

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.182 AC: 46963 AN: 257564 Hom.: 1846 Cov.: 0 AF XY: 0.193 AC XY: 24345 AN XY: 125984

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

African (AFR) AF: 0.205 AC: 2518 AN: 12290

American (AMR) AF: 0.369 AC: 1679 AN: 4546

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 1182 AN: 4270

East Asian (EAS) AF: 0.386 AC: 864 AN: 2238

South Asian (SAS) AF: 0.381 AC: 5091 AN: 13352

European-Finnish (FIN) AF: 0.403 AC: 3372 AN: 8358

Middle Eastern (MID) AF: 0.334 AC: 499 AN: 1494

European-Non Finnish (NFE) AF: 0.147 AC: 29358 AN: 200094

Other (OTH) AF: 0.220 AC: 2400 AN: 10922

⚠️ 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: 0.264 AC: 7069 AN: 26768 Hom.: 240 Cov.: 0 AF XY: 0.276 AC XY: 3596 AN XY: 13006

African (AFR) AF: 0.207 AC: 2862 AN: 13812

American (AMR) AF: 0.311 AC: 648 AN: 2084

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 171 AN: 534

East Asian (EAS) AF: 0.438 AC: 85 AN: 194

South Asian (SAS) AF: 0.469 AC: 319 AN: 680

European-Finnish (FIN) AF: 0.407 AC: 746 AN: 1834

Middle Eastern (MID) AF: 0.286 AC: 20 AN: 70

European-Non Finnish (NFE) AF: 0.294 AC: 2081 AN: 7072

Other (OTH) AF: 0.278 AC: 116 AN: 418

Alfa AF: 0.828 Hom.: 65485

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	DICER1-related tumor predisposition (3)
-	-	1	Euthyroid goiter (1)
-	-	1	Euthyroid goiter;C1266144:Pleuropulmonary blastoma;C1867234:Rhabdomyosarcoma, embryonal, 2;C4748924:Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome (1)
-	-	1	not provided (1)
-	-	1	Pleuropulmonary blastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.59
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1778057; hg19: chr14-95566108; COSMIC: COSV58616728; COSMIC: COSV58616728;