rs1060503648

Variant names:

• chr14-95096643-C-A
• rs1060503648
• NM_177438.3:c.4277G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95096643-C-A
• chr14-95096643-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_177438.3(DICER1):​c.4277G>T​(p.Ser1426Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1426N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.311
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057067007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.4277G>T	p.Ser1426Ile	missense_variant	Exon 23 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.4277G>T	p.Ser1426Ile	missense_variant	Exon 23 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460024 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726272

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111186

Other (OTH) AF: 0.0000166 AC: 1 AN: 60276

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.46
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;T;T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.84	.;.;T;.;T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.057	T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.34	N;N;N;N;.;N
PhyloP100		0.31
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.65	N;N;N;N;N;N
REVEL	Benign	0.047
Sift	Uncertain	0.010	D;D;D;D;T;D
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.0060	B;B;B;B;.;.
Vest4		0.13
MutPred		0.43		Loss of phosphorylation at S1426 (P = 0.0084);Loss of phosphorylation at S1426 (P = 0.0084);Loss of phosphorylation at S1426 (P = 0.0084);Loss of phosphorylation at S1426 (P = 0.0084);.;Loss of phosphorylation at S1426 (P = 0.0084);
MVP		0.67
MPC		0.58
ClinPred		0.085	T
GERP RS		-3.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.087
gMVP		0.16
Mutation Taster		=91/9	polymorphism

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: rs1060503648; hg19: chr14-95562980;