chr14-95099762-ACACACACAC-A

Variant names:

• chr14-95099762-ACACACACAC-A
• rs772457274
• NM_177438.3:c.4206+9_4206+17delGTGTGTGTG

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+9_4206+17delGTGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,253,814 control chromosomes in the GnomAD database, including 102 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (52 hom., cov: 0)
  • Exomes 𝑓: 0.0044 (50 hom.)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.918
• 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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 14-95099762-ACACACACAC-A is Benign according to our data. Variant chr14-95099762-ACACACACAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 477186.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 = 0.0172 (2085/121112) while in subpopulation AFR AF = 0.0474 (1733/36580). AF 95% confidence interval is 0.0455. There are 52 homozygotes in GnomAd4. There are 1004 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2085 AD,Unknown gene.

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+9_4206+17delGTGTGTGTG		intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+9_4206+17delGTGTGTGTG		intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+9_4206+17delGTGTGTGTG		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+9_4206+17delGTGTGTGTG		intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+9_4206+17delGTGTGTGTG		intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+9_4206+17delGTGTGTGTG		intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2079 AN: 121006 Hom.: 52 Cov.: 0

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00764

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.00513

Gnomad FIN AF: 0.00479

Gnomad MID AF: 0.0155

Gnomad NFE AF: 0.00283

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00303 AC: 699 AN: 230604 AF XY: 0.00249

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.000841

Gnomad EAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00226

GnomAD4 exome AF: 0.00445 AC: 5039 AN: 1132702 Hom.: 50 AF XY: 0.00438 AC XY: 2460 AN XY: 561494

African (AFR) AF: 0.0479 AC: 1397 AN: 29168

American (AMR) AF: 0.00437 AC: 136 AN: 31106

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 13 AN: 19966

East Asian (EAS) AF: 0.0219 AC: 289 AN: 13222

South Asian (SAS) AF: 0.00515 AC: 314 AN: 60932

European-Finnish (FIN) AF: 0.00508 AC: 197 AN: 38762

Middle Eastern (MID) AF: 0.0153 AC: 69 AN: 4498

European-Non Finnish (NFE) AF: 0.00256 AC: 2273 AN: 888700

Other (OTH) AF: 0.00757 AC: 351 AN: 46348

GnomAD4 genome AF: 0.0172 AC: 2085 AN: 121112 Hom.: 52 Cov.: 0 AF XY: 0.0172 AC XY: 1004 AN XY: 58326

African (AFR) AF: 0.0474 AC: 1733 AN: 36580

American (AMR) AF: 0.00762 AC: 83 AN: 10888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.0157 AC: 32 AN: 2036

South Asian (SAS) AF: 0.00513 AC: 18 AN: 3508

European-Finnish (FIN) AF: 0.00479 AC: 38 AN: 7936

Middle Eastern (MID) AF: 0.00833 AC: 2 AN: 240

European-Non Finnish (NFE) AF: 0.00283 AC: 155 AN: 54754

Other (OTH) AF: 0.0143 AC: 24 AN: 1680

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	DICER1-related tumor predisposition (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.92
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: rs772457274; hg19: chr14-95566099;