rs1060503657
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.4412C>T variant in DICER1 is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 1471 (p.Pro1471Leu). 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/GTRs). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00001543 (1/64,794 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.04 MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4, BS2_Supporting. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614180/MONDO:0100216/024
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.4412C>T | p.Pro1471Leu | missense_variant | 23/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.4412C>T | p.Pro1471Leu | missense_variant | 23/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251324Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135850
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461764Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727190
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 06, 2022 | The DICER1 c.4412C>T; p.Pro1471Leu variant (rs1060503657), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 412179). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 1471 is moderately conserved, and computational analyses predict that this variant is neutral (REVEL: 0.04). However, given the lack of clinical and functional data, the significance of the p.Pro1471Leu variant is uncertain at this time. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 06, 2023 | The p.P1471L variant (also known as c.4412C>T), located in coding exon 22 of the DICER1 gene, results from a C to T substitution at nucleotide position 4412. The proline at codon 1471 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 13, 2022 | - - |
DICER1-related tumor predisposition Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1471 of the DICER1 protein (p.Pro1471Leu). This variant is not present in population databases (gnomAD no frequency). 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: 412179). 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. - |
Likely benign, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | Jan 09, 2024 | The NM_177438.2:c.4412C>T variant in DICER1 is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 1471 (p.Pro1471Leu). 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/GTRs). The highest population minor allele frequency in gnomAD v3.1.2 is 0.00001543 (1/64,794 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.04 MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4, BS2_Supporting. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at