owencqueen/cgbench_data huggingface dataset:
Gene: UBE3A (HGNC:12496)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




Use as defined by ClinGen SVI working group (PMID:30192042).


PVS1 is applicable for any truncating variant up to p.K841, for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, for canonical splice site variants predicted to result in an out-of-frame product, and for intragenic deletions/duplications predicted to result in an out-of-frame product.
Gene: UBE3A (HGNC:12496)
Evidence Code: PVS1 — Strong
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons).
Gene: UBE3A (HGNC:12496)
Evidence Code: PS2 — Very Strong
Modification Type: None
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.




≥2 independent occurrences of PS2.


≥2 independent occurrences of PM6 and one occurrence of PS2.


Evidence from literature must be fully evaluated to support independent events.
Gene: UBE3A (HGNC:12496)
Evidence Code: PS2 — Strong
Modification Type: None
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.




1 occurrence of PS2.
Gene: UBE3A (HGNC:12496)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies supportive of a damaging effect.




RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).


See included table for acceptable functional studies.
Gene: UBE3A (HGNC:12496)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Located in a mutational hot spot and/or critical and well-established functional domain.




3’ cysteine binding site: aa 820 (PMID 9887341)
Gene: UBE3A (HGNC:12496)
Evidence Code: PM4 — Strong
Modification Type: Disease-specific
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.




PM4_Strong is applicable to stop-loss variants in UBE3A, as several stop loss variants in this gene has been described in affected individuals PMID 25212744.
Gene: UBE3A (HGNC:12496)
Evidence Code: PM4 — Supporting
Modification Type: Strength
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.




Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domain for this gene).
Gene: UBE3A (HGNC:12496)
Evidence Code: PM6 — Very Strong
Modification Type: Strength
Assumed de novo without confirmation of paternity and maternity.




≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.
Gene: UBE3A (HGNC:12496)
Evidence Code: PM6 — Strong
Modification Type: Strength
Assumed de novo without confirmation of paternity and maternity.




≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.
Gene: UBE3A (HGNC:12496)
Evidence Code: PM6 — Moderate
Modification Type: None
Assumed de novo without confirmation of paternity and maternity.




1 occurrence of PM6.
Gene: UBE3A (HGNC:12496)
Evidence Code: PP1 — Strong
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




≥5 informative meiosis.
Gene: UBE3A (HGNC:12496)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




3-4 informative meiosis.
Gene: UBE3A (HGNC:12496)
Evidence Code: PP1 — Supporting
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




2 informative meiosis.
Gene: UBE3A (HGNC:12496)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency greater than expected for disorder.




Use large population databases (i.e. gnomAD).


Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.


Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.
Gene: UBE3A (HGNC:12496)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.




RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.


Not applicable for other functional studies (see tables for other accepted functional studies).
Gene: UBE3A (HGNC:12496)
Evidence Code: BS4 — Strong
Modification Type: Strength
Lack of segregation in affected members of a family.




Absent in a similarly affected family member, when seen in two or more families.
Gene: UBE3A (HGNC:12496)
Evidence Code: BS4 — Supporting
Modification Type: Strength
Lack of segregation in affected members of a family.




Absent in a similarly affected family member.
Gene: UBE3A (HGNC:12496)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
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.




BP2 is not applicable for UBE3A in trans state.
Gene: UBE3A (HGNC:12496)
Evidence Code: BP5 — Supporting
Modification Type: Disease-specific
Variant found in a case with an alternate molecular basis for disease.




≥1 cases with alternate molecular basis for disease.