rs1060503594
Variant summary
Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_177438.3(DICER1):c.1423A>T variant in DICER1 is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 475 (p.Ser475Cys). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002670 (2/74916 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.568, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 06/25/24). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614383/MONDO:0100216/024
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.1423A>T | p.Ser475Cys | missense_variant | 9/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.1423A>T | p.Ser475Cys | missense_variant | 9/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251352Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461550Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727094
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Uncertain:1Benign:1
Uncertain significance, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | Jun 25, 2024 | The NM_177438.3(DICER1):c.1423A>T variant in DICER1 is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 475 (p.Ser475Cys). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002670 (2/74916 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.568, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 06/25/24). - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 17, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2022 | The p.S475C variant (also known as c.1423A>T), located in coding exon 8 of the DICER1 gene, results from an A to T substitution at nucleotide position 1423. The serine at codon 475 is replaced by cysteine, an amino acid with dissimilar 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