14-95124594-T-G

Variant names:

• chr14-95124594-T-G
• rs781090715
• NM_177438.3:c.978A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_177438.3(DICER1):​c.978A>C​(p.Val326Val) variant causes a synonymous 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V326V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.55
• Publications: 1 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-95124594-T-G is Benign according to our data. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95124594-T-G is described in CliVar as Likely_benign. Clinvar id is 1153787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.55 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.978A>C	p.Val326Val	synonymous_variant	Exon 8 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.978A>C	p.Val326Val	synonymous_variant	Exon 8 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Benign:1

Dec 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jun 30, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.48
DANN	Benign	0.69
PhyloP100		-1.5

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: rs781090715; hg19: chr14-95590931;