NM_177438.3:c.184G>A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_177438.3(DICER1):c.184G>A(p.Val62Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,744 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152086Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251332Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135836
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461658Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727142
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152086Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74282
ClinVar
Submissions by phenotype
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with rhabdomyosarcoma as well as a child with Cushing's disease and a corticotropinoma whose tumor did not demonstrate loss of heterozygosity or a second DICER1 variant (Zhang et al., 2015; Martinez de LaPiscina et al., 2020); This variant is associated with the following publications: (PMID: 27819237, 26580448, 27050224, 28748527, 32714280) -
DICER1-related tumor predisposition Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 62 of the DICER1 protein (p.Val62Ile). This variant is present in population databases (rs746671039, gnomAD 0.007%). This missense change has been observed in individual(s) with corticotropinoma and/or rhabdomyosarcoma (PMID: 27050224, 27819237, 32714280, 36149413). ClinVar contains an entry for this variant (Variation ID: 543572). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.V62I variant (also known as c.184G>A), located in coding exon 2 of the DICER1 gene, results from a G to A substitution at nucleotide position 184. The valine at codon 62 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a pediatric patient diagnosed with rhabdosarcoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This alteration was also detected in a Brazilian patient diagnosed with Cushing's disease with corticotropinoma (Martínez de LaPiscina I et al. Front Endocrinol (Lausanne), 2020 Jul;11:433). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Benign:1
ACMG criteria met: BS1, BP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at