NM_177438.3:c.*3473T>C

Variant names:

• chr14-95087025-A-G
• rs3742330
• NM_177438.3:c.*3473T>C

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.*3473T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 233,008 control chromosomes in the GnomAD database, including 2,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1023 hom., cov: 33)
  • Exomes 𝑓: 0.14 (1467 hom.)
• Consequence: DICER1 NM_177438.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.377
• Publications: 92 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-95087025-A-G is Benign according to our data. Variant chr14-95087025-A-G is described in ClinVar as Benign. ClinVar VariationId is 315050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 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.*3473T>C		3_prime_UTR	Exon 27 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.*3473T>C		3_prime_UTR	Exon 27 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.*3473T>C		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.*3473T>C		3_prime_UTR	Exon 27 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000529720.2	TSL:1	c.*3473T>C		3_prime_UTR	Exon 30 of 30	ENSP00000433926.2	Q9UPY3-1
	DICER1	ENST00000531162.7	TSL:1	c.*3473T>C		3_prime_UTR	Exon 29 of 29	ENSP00000433060.3	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0923 AC: 14040 AN: 152154 Hom.: 1021 Cov.: 33

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0909

Gnomad OTH AF: 0.0919

GnomAD4 exome AF: 0.140 AC: 11309 AN: 80736 Hom.: 1467 Cov.: 0 AF XY: 0.139 AC XY: 5155 AN XY: 37132

African (AFR) AF: 0.0224 AC: 87 AN: 3876

American (AMR) AF: 0.128 AC: 319 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 498 AN: 5106

East Asian (EAS) AF: 0.453 AC: 5126 AN: 11324

South Asian (SAS) AF: 0.172 AC: 120 AN: 696

European-Finnish (FIN) AF: 0.0980 AC: 20 AN: 204

Middle Eastern (MID) AF: 0.120 AC: 59 AN: 492

European-Non Finnish (NFE) AF: 0.0885 AC: 4407 AN: 49816

Other (OTH) AF: 0.0999 AC: 673 AN: 6738

GnomAD4 genome AF: 0.0922 AC: 14039 AN: 152272 Hom.: 1023 Cov.: 33 AF XY: 0.0988 AC XY: 7355 AN XY: 74452

African (AFR) AF: 0.0281 AC: 1170 AN: 41580

American (AMR) AF: 0.144 AC: 2208 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3470

East Asian (EAS) AF: 0.377 AC: 1953 AN: 5174

South Asian (SAS) AF: 0.147 AC: 706 AN: 4816

European-Finnish (FIN) AF: 0.114 AC: 1209 AN: 10596

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0909 AC: 6186 AN: 68020

Other (OTH) AF: 0.0909 AC: 192 AN: 2112

Alfa AF: 0.0944 Hom.: 1538

Bravo AF: 0.0900

Asia WGS AF: 0.225 AC: 782 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.46
PhyloP100		0.38
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: rs3742330; hg19: chr14-95553362;