rs1060503602
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_177438.3(DICER1):āc.1004A>Gā(p.His335Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,790 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H335Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.1004A>G | p.His335Arg | missense_variant | 8/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.1004A>G | p.His335Arg | missense_variant | 8/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248634Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134716
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461556Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727058
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74382
ClinVar
Submissions by phenotype
Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 10, 2023 | - - |
DICER1-related tumor predisposition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 09, 2023 | This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 335 of the DICER1 protein (p.His335Arg). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DICER1 protein function. ClinVar contains an entry for this variant (Variation ID: 412072). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | The p.H335R variant (also known as c.1004A>G), located in coding exon 7 of the DICER1 gene, results from an A to G substitution at nucleotide position 1004. The histidine at codon 335 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at