NM_177438.3:c.897G>T

Variant names:

• chr14-95126586-C-A
• rs201842071
• NM_177438.3:c.897G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_177438.3(DICER1):​c.897G>T​(p.Ser299Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000294 in 1,360,504 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S299S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: DICER1 NM_177438.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.773
• Publications: 2 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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 14-95126586-C-A is Benign according to our data. Variant chr14-95126586-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 758581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.773 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.897G>T	p.Ser299Ser	synonymous_variant	Exon 7 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.897G>T	p.Ser299Ser	synonymous_variant	Exon 7 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000294 AC: 4 AN: 1360504 Hom.: 0 Cov.: 27 AF XY: 0.00000440 AC XY: 3 AN XY: 682042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31300

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25506

East Asian (EAS) AF: 0.00 AC: 0 AN: 39090

South Asian (SAS) AF: 0.00 AC: 0 AN: 83888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5314

European-Non Finnish (NFE) AF: 0.00000294 AC: 3 AN: 1020656

Other (OTH) AF: 0.0000176 AC: 1 AN: 56926

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.007872), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Benign:1

Oct 11, 2023

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 27, 2023

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	-0.40
CADD	Benign	5.4
DANN	Benign	0.64
PhyloP100		0.77

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: rs201842071; hg19: chr14-95592923;