14-95133331-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS2_SupportingBP4
This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.128C>T variant in DICER1 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 43 (p.Thr43Met). 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 silico tools predict no damaging impact of the variant on protein function (REVEL: 0.429; MaxEntScan and SpliceAI: no effect on splicing) (BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0002667 (16/59982 alleles) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 06/25/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7331742/MONDO:0100216/024
Frequency
Consequence
NM_001395686.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000803 AC: 20AN: 248964Hom.: 0 AF XY: 0.0000816 AC XY: 11AN XY: 134786
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461780Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 727188
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74308
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 16, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2023 | The p.T43M variant (also known as c.128C>T), located in coding exon 1 of the DICER1 gene, results from a C to T substitution at nucleotide position 128. The threonine at codon 43 is replaced by methionine, an amino acid with 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. - |
DICER1-related tumor predisposition Benign:2
Likely benign, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | Jun 25, 2024 | The NM_177438.2:c.128C>T variant in DICER1 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 43 (p.Thr43Met). 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 silico tools predict no damaging impact of the variant on protein function (REVEL: 0.429; MaxEntScan and SpliceAI: no effect on splicing) (BP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0002667 (16/59982 alleles) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 06/25/2024) - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 03, 2025 | - - |
Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Euthyroid goiter;C1266144:Pleuropulmonary blastoma;C1867234:Rhabdomyosarcoma, embryonal, 2;C4748924:Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 15, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2023 | 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 - |
Euthyroid goiter Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 03, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at