NM_177438.3:c.255C>G

Variant names:

• chr14-95132567-G-C
• rs763422772
• NM_177438.3:c.255C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_177438.3(DICER1):​c.255C>G​(p.Ile85Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. I85V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.39
• Publications: 6 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11369109).
• BP6: Variant 14-95132567-G-C is Benign according to our data. Variant chr14-95132567-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242065.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000356 (52/1461674) while in subpopulation AMR AF = 0.0011 (49/44722). AF 95% confidence interval is 0.000851. There are 0 homozygotes in GnomAdExome4. There are 21 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 52 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.255C>G	p.Ile85Met	missense	Exon 3 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001395686.1		c.-20C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 27	NP_001382615.1
	DICER1	NM_001395687.1		c.-20C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 25	NP_001382616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.255C>G	p.Ile85Met	missense	Exon 3 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.255C>G	p.Ile85Met	missense	Exon 5 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.255C>G	p.Ile85Met	missense	Exon 3 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 251384 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461674 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00110 AC: 49 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111900

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.000196 AC: 3 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000181 AC: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	1	DICER1-related disorder (1)
-	-	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	0.23
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.040	N
REVEL	Pathogenic	0.66
Sift	Benign	0.34	T
Sift4G	Benign	0.21	T
Polyphen		0.047	B
Vest4		0.62
MVP		0.55
MPC		0.83
ClinPred		0.049	T
GERP RS		4.9
Varity_R		0.49
gMVP		0.67
Mutation Taster		=12/88	disease causing

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: rs763422772; hg19: chr14-95598904; COSMIC: COSV58617794;