chr14-95095975-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BS1_SupportingBS2
The NM_177438.3(DICER1):c.4945A>G(p.Met1649Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,614,254 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1649I) has been classified as Uncertain significance.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.4945A>G | p.Met1649Val | missense_variant | 23/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.4945A>G | p.Met1649Val | missense_variant | 23/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251432Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727248
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152362Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74518
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1649 of the DICER1 protein (p.Met1649Val). This variant is present in population databases (rs146715213, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 412129). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 12, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 02, 2023 | The p.M1649V variant (also known as c.4945A>G), located in coding exon 22 of the DICER1 gene, results from an A to G substitution at nucleotide position 4945. The methionine at codon 1649 is replaced by valine, an amino acid with highly similar properties. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at