chr14-95133410-T-G

Variant names:

• chr14-95133410-T-G
• rs1555376587
• NM_177438.3:c.49A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001395686.1(DICER1):​c.-226A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene DICER1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DICER1 NM_001395686.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.23
• 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

Specifications for DICER1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12964165).
• BP6: Variant 14-95133410-T-G is Benign according to our data. Variant chr14-95133410-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 543588.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395686.1. 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.49A>C	p.Met17Leu	missense	Exon 2 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001395686.1		c.-226A>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 27	NP_001382615.1
	DICER1	NM_001395688.1		c.-226A>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 28	NP_001382617.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.49A>C	p.Met17Leu	missense	Exon 2 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.49A>C	p.Met17Leu	missense	Exon 4 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.49A>C	p.Met17Leu	missense	Exon 2 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	DICER1-related tumor predisposition (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.11
Sift	Benign	0.26	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.28		Loss of disorder (P = 0.0797)
MVP		0.60
MPC		0.46
ClinPred		0.27	T
GERP RS		3.1
PromoterAI		-0.019	Neutral
Varity_R		0.12
gMVP		0.32
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555376587; hg19: chr14-95599747;