rs967583633

chr14-95115807-C-Gchr14-95115807-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_177438.3(DICER1):c.1767G>C(p.Lys589Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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. K589R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DICER1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.1767G>C	p.Lys589Asn	missense_variant	11/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.1767G>C	p.Lys589Asn	missense_variant	11/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;D;D;D;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.068	T;T;T;T;T
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.55	P;P;P;P;.
Vest4		0.73
MutPred		0.50		Loss of methylation at K589 (P = 0.0028);Loss of methylation at K589 (P = 0.0028);Loss of methylation at K589 (P = 0.0028);Loss of methylation at K589 (P = 0.0028);Loss of methylation at K589 (P = 0.0028);
MVP		0.61
MPC		0.84
ClinPred		0.88	D
GERP RS		-5.9
Varity_R		0.31
gMVP		0.73

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-95582144;