chr14-95087533-AC-A

Variant names:

• chr14-95087533-AC-A
• rs537009606
• NM_177438.3:c.*2964delG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_177438.3(DICER1):​c.*2964delG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000429 in 233,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: DICER1 NM_177438.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000348 (53/152196) while in subpopulation NFE AF = 0.000632 (43/68040). AF 95% confidence interval is 0.000482. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 53 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.*2964delG		3_prime_UTR	Exon 27 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.*2964delG		3_prime_UTR	Exon 27 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.*2964delG		3_prime_UTR	Exon 27 of 27	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.*2964delG		3_prime_UTR	Exon 27 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000529720.2	TSL:1	c.*2964delG		3_prime_UTR	Exon 30 of 30	ENSP00000433926.2	Q9UPY3-1
	DICER1	ENST00000531162.7	TSL:1	c.*2964delG		3_prime_UTR	Exon 29 of 29	ENSP00000433060.3	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

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: 0.000632

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000581 AC: 47 AN: 80854 Hom.: 0 Cov.: 0 AF XY: 0.000619 AC XY: 23 AN XY: 37158

African (AFR) AF: 0.000514 AC: 2 AN: 3892

American (AMR) AF: 0.00 AC: 0 AN: 2498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5120

East Asian (EAS) AF: 0.00 AC: 0 AN: 11348

South Asian (SAS) AF: 0.00 AC: 0 AN: 700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 60

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 492

European-Non Finnish (NFE) AF: 0.000860 AC: 43 AN: 49982

Other (OTH) AF: 0.000296 AC: 2 AN: 6762

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74354

African (AFR) AF: 0.000241 AC: 10 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000374

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pleuropulmonary blastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

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: rs537009606; hg19: chr14-95553870;