owencqueen/cgbench_data huggingface dataset:
Gene: DICER1 (HGNC:17098)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific,General recommendation
Follow SVI guidance, using DICER1-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018
1
, the following will apply:




Nonsense or frameshift variants:


PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.


PVS1_Moderate applies to variants resulting in protein truncation 3’ of this cutoff


Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:


Exon 10 SDS/SAS: PVS1_Strong (in-frame but exon includes >10% protein)


Exons 5, 15, 18, 22 SDS/SAS: PVS1_Moderate (in-frame and each <10% of protein)


Exon 27 SAS: PVS1_Moderate (final exon)


Exon 1: no criteria (non-coding)


Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without DICER1 phenotype. SDS = splice donor site; SAS = splice acceptor site. Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3. A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
≥4 de novo points
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Strong
Modification Type: Strength
≥2 but less than 4 de novo points
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Moderate
Modification Type: General recommendation
≥1 but less than 2 de novo points
Gene: DICER1 (HGNC:17098)
Evidence Code: PS2 — Supporting
Modification Type: Strength
≥0.5 but less than 1 de novo points
Gene: DICER1 (HGNC:17098)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption. (PS3_Moderate if PVS1_Strong is applied).
Gene: DICER1 (HGNC:17098)
Evidence Code: PS3 — Moderate
Modification Type: Disease-specific,General recommendation
RNA assay shows in-frame splicing impact with change in protein length <193 residues AND RNase IIIb domain not disrupted.
Gene: DICER1 (HGNC:17098)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific,Strength
In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed).
Gene: DICER1 (HGNC:17098)
Evidence Code: PS4 — Strong
Modification Type: General recommendation
≥4 phenotype points
Gene: DICER1 (HGNC:17098)
Evidence Code: PS4 — Moderate
Modification Type: Strength
2 – 3.5 phenotype points
Gene: DICER1 (HGNC:17098)
Evidence Code: PS4 — Supporting
Modification Type: Strength
1 – 1.5 phenotype points
Gene: DICER1 (HGNC:17098)
Evidence Code: PP1 — Strong
Modification Type: Strength
≥7 meioses across ≥2 families
Gene: DICER1 (HGNC:17098)
Evidence Code: PP1 — Moderate
Modification Type: Strength
5 – 6 meioses across ≥1 family
Gene: DICER1 (HGNC:17098)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation
3 – 4 meioses across ≥1 family
Gene: DICER1 (HGNC:17098)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants. Tumor testing
6
 of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the following:




A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) AND


Retention of the germline DICER1 variant under evaluation. PP4 is NOT applicable if:


The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR


Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis).
Gene: DICER1 (HGNC:17098)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific
For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.)
Gene: DICER1 (HGNC:17098)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific
An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018
7
.