rs765551529

Variant names:

• chr14-95115670-T-C
• rs765551529
• NM_177438.3:c.1904A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.1904A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by serine at amino acid 635 (p.Asp635Ser). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; PMIDs: 33718253, Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 (non-cancer) is 0.00001 (1/91082 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). While in silico tools do not predict damaging impact of the variant on protein function (REVEL: 0.398), the splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3. (Bayesian Points: 1; VCEP specifications version 1.3.0; 01/07/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7331374/MONDO:0100216/024

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 7.81
• 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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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.1904A>G	p.Asn635Ser	missense	Exon 11 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.1904A>G	p.Asn635Ser	missense	Exon 11 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.1904A>G	p.Asn635Ser	missense	Exon 11 of 27	NP_001278557.1	Q9UPY3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.1904A>G	p.Asn635Ser	missense	Exon 11 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.1904A>G	p.Asn635Ser	missense	Exon 13 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.1904A>G	p.Asn635Ser	missense	Exon 11 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251466 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	DICER1-related tumor predisposition (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.81	P
Vest4		0.92
MutPred		0.67		Gain of helix (P = 0.2059)
MVP		0.78
MPC		1.2
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.85
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765551529; hg19: chr14-95582007;