rs117358479

Variant names:

• chr14-95133439-T-C
• rs117358479
• NM_177438.3:c.20A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_030621.4(DICER1):​c.20A>G​(p.Gln7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,613,722 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q7K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (4 hom.)
• Consequence: DICER1 NM_030621.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18 O:1
• Conservation: PhyloP100: 1.93
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007442862).
• BP6: Variant 14-95133439-T-C is Benign according to our data. Variant chr14-95133439-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133962.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00167 (255/152316) while in subpopulation NFE AF = 0.00323 (220/68022). AF 95% confidence interval is 0.00288. There are 1 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 255 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030621.4. 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.20A>G	p.Gln7Arg	missense	Exon 2 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.20A>G	p.Gln7Arg	missense	Exon 2 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.20A>G	p.Gln7Arg	missense	Exon 2 of 27	NP_001278557.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.20A>G	p.Gln7Arg	missense	Exon 2 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.20A>G	p.Gln7Arg	missense	Exon 4 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.20A>G	p.Gln7Arg	missense	Exon 2 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00169 AC: 420 AN: 248074 AF XY: 0.00189

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.00238 AC: 3483 AN: 1461406 Hom.: 4 Cov.: 31 AF XY: 0.00246 AC XY: 1791 AN XY: 726920

African (AFR) AF: 0.000239 AC: 8 AN: 33474

American (AMR) AF: 0.000985 AC: 44 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00178 AC: 153 AN: 86156

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53378

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00279 AC: 3097 AN: 1111778

Other (OTH) AF: 0.00215 AC: 130 AN: 60380

GnomAD4 genome AF: 0.00167 AC: 255 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74476

African (AFR) AF: 0.000192 AC: 8 AN: 41578

American (AMR) AF: 0.000719 AC: 11 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00323 AC: 220 AN: 68022

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00259 Hom.: 1

Bravo AF: 0.00175

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00161 AC: 196

EpiCase AF: 0.00305

EpiControl AF: 0.00226

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	8	not provided (9)
-	-	3	DICER1-related tumor predisposition (3)
-	-	3	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Breast neoplasm (1)
-	-	1	Pleuropulmonary blastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.048
Sift	Benign	0.032	D
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.22
MVP		0.56
MPC		0.53
ClinPred		0.0063	T
GERP RS		1.8
PromoterAI		-0.0060	Neutral
Varity_R		0.055
gMVP		0.71
Mutation Taster		=81/19	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: rs117358479; hg19: chr14-95599776; COSMIC: COSV58626575;