chr14-95103548-A-G

Variant names:

• chr14-95103548-A-G
• rs754352488
• NM_177438.3:c.3848T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000343455.8(DICER1):​c.3848T>C​(p.Ile1283Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1283V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DICER1 ENST00000343455.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.00600
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047151).
• BS2: High AC in GnomAdExome4 at 8 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000343455.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.3848T>C	p.Ile1283Thr	missense	Exon 21 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.3848T>C	p.Ile1283Thr	missense	Exon 21 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.3848T>C	p.Ile1283Thr	missense	Exon 21 of 27	NP_001278557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.3848T>C	p.Ile1283Thr	missense	Exon 21 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.3848T>C	p.Ile1283Thr	missense	Exon 23 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.3848T>C	p.Ile1283Thr	missense	Exon 21 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251310 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	DICER1-related tumor predisposition (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.1
DANN	Benign	0.54
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.0060
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.041
Sift	Benign	0.55	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.44		Gain of glycosylation at I1283 (P = 0.012)
MVP		0.43
MPC		0.62
ClinPred		0.013	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.019
gMVP		0.21
Mutation Taster		=95/5	polymorphism

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: rs754352488; hg19: chr14-95569885;