owencqueen/cgbench_data huggingface dataset:
Gene: IDUA (HGNC:5391)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific,Strength
The same assays outlined for PS3 will be used for BS3. Please see PS3 guidance for additional information on these assays. 


BS3_Supporting can be applied for expression of IDUA sequence variants in cultured cells and subsequent measurement of enzyme activity provided that there is no other evidence to suggest that the variant could be disease-causing e.g. mislocalization (see Appendix 3 for thresholds for specific studies: >10% activity (Beesley et al, 2001, PMID: 11735025; Yogalingam et al, 2004, PMID: 15300847; Matte et al, 2003); >~10% activity / enzyme abundance (Yu et al, 2020. PMID: 33198351).
Gene: IDUA (HGNC:5391)
Evidence Code: BS4 — Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.
Gene: IDUA (HGNC:5391)
Evidence Code: BS4 — Strong
Modification Type: None
Non-segregation with disease in a family i.e. variant is absent in an affected individual.
Gene: IDUA (HGNC:5391)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: IDUA (HGNC:5391)
Evidence Code: BP2 — Original ACMG Summary
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Gene: IDUA (HGNC:5391)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: IDUA (HGNC:5391)
Evidence Code: BP4 — Original ACMG Summary
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
Gene: IDUA (HGNC:5391)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
Missense changes with a REVEL score < 0.290 (threshold based on Pejaver et al; however, BP4 will only be applied at the supporting level). 


For in frame insertions and deletions, use PROVEAN (
http://provean.jcvi.org/seq_submit.php
 ; score >-2.5), Mutation Taster (
http://www.mutationtaster.org/
 ; count if “polymorphism”, and MutPred-Indel (
http://mutpredindel.cs.indiana.edu/
 ; score <0.5. Apply BP4 if all predictors indicate that the variant is benign.


For non-canonical splice site variants, use SpliceAI (
https://spliceailookup.broadinstitute.org/
 ) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. This criterion can be applied as PP3 (Splicing) for SpliceAI scores ≤0.1 (based on Walker et al, PMID: 37352859). 


If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.
Gene: IDUA (HGNC:5391)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: IDUA (HGNC:5391)
Evidence Code: BP6 — Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: IDUA (HGNC:5391)
Evidence Code: BP7 — Original ACMG Summary
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Gene: IDUA (HGNC:5391)
Evidence Code: BP7 — Strong
Modification Type: Strength
Experimental evidence (RT-PCR, RNA Seq, minigene) shows that the variant does not impact splicing. BP7_Strong (RNA) will be used only under strict circumstances in which it is clear that the allele with the variant is expressed at the normal level to avoid counting a “normal” result because the allele with the variant is absent due to nonsense-mediated decay (Walker et al, PMID: 37352859).
Gene: IDUA (HGNC:5391)
Evidence Code: BP7 — Supporting
Modification Type: None
BP7 can be applied if the variant is synonymous, unless the variant is in the first nucleotide or last three nucleotides of an exon, AND BP4 is met i.e. SpliceAI predicts no impact on splicing (score ≤ 0.10)