owencqueen/cgbench_data huggingface dataset:
Gene: F8 (HGNC:3546)
Evidence Code: PVS1 — Original ACMG Summary
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Caveats:
 • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
 • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
 • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
 • Use caution in the presence of multiple transcripts.
Gene: F8 (HGNC:3546)
Evidence Code: PVS1 — Very Strong
Modification Type: General recommendation
Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.
Gene: F8 (HGNC:3546)
Evidence Code: PVS1 — Strong
Modification Type: General recommendation
Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.
Gene: F8 (HGNC:3546)
Evidence Code: PVS1 — Moderate
Modification Type: General recommendation
Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.
Gene: F8 (HGNC:3546)
Evidence Code: PS1 — Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: F8 (HGNC:3546)
Evidence Code: PS1 — Strong
Modification Type: General recommendation
This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on 
F8
 gene rule specifications from the Coagulation Factor Deficiency VCEP and where 
in silico
 predictors do not suggest a splicing defect.
Gene: F8 (HGNC:3546)
Evidence Code: PS1 — Moderate
Modification Type: General recommendation
This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on 
F8
 gene rule specifications from the Coagulation Factor Deficiency VCEP and where 
in silico
 predictors do not suggesting a splicing defect.
Gene: F8 (HGNC:3546)
Evidence Code: PS2 — Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Gene: F8 (HGNC:3546)
Evidence Code: PS2 — Very Strong
Modification Type: Disease-specific
Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value.
Gene: F8 (HGNC:3546)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific
Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value.
Gene: F8 (HGNC:3546)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific
Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value.
Gene: F8 (HGNC:3546)
Evidence Code: PS2 — Supporting
Modification Type: Disease-specific
Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value.
Gene: F8 (HGNC:3546)
Evidence Code: PS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
Gene: F8 (HGNC:3546)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
Abnormal factor VIII activity (<40 IU/dL or 40%) via one-stage or two-stage chromogenic assay in a cell line and/or mouse model.
Gene: F8 (HGNC:3546)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific
Absent or significantly reduced factor VIII antigen levels compared to wildtype in a cell line by quantitative assay.
Gene: F8 (HGNC:3546)
Evidence Code: PS4 — Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
Gene: F8 (HGNC:3546)
Evidence Code: PS4 — Very Strong
Modification Type: Disease-specific
≥8 probands meet criteria described below
Gene: F8 (HGNC:3546)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific
4-7 probands meet criteria described below
Gene: F8 (HGNC:3546)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific
2-3 probands meet criteria described below
Gene: F8 (HGNC:3546)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific
1 proband meets criteria described below
Gene: F8 (HGNC:3546)
Evidence Code: PM1 — Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Gene: F8 (HGNC:3546)
Evidence Code: PM1 — Strong
Modification Type: Gene-specific
This code can be applied at the strong level for variants involving the following residues: R391-S392, R759-S760, E1701-Q1705, R1708-S1709, Y1683, Y1689, Y737, Y742.
Gene: F8 (HGNC:3546)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific
This code can be applied at the moderate level for variants involving the following residues: 


Residues affecting secretion: Arg1667, Arg1332


FXa-binding residues: Gly2267-Gly2304 (with the exception of Ser2283)
Gene: F8 (HGNC:3546)
Evidence Code: PM2 — Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Caveat: Population data for indels may be poorly called by next generation sequencing.
Gene: F8 (HGNC:3546)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific
Variant must be absent in males in population databases, such as gnomAD.
Gene: F8 (HGNC:3546)
Evidence Code: PM3 — Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
Gene: F8 (HGNC:3546)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: F8 (HGNC:3546)
Evidence Code: PM4 — Moderate
Modification Type: None
Use code with no specification.
Gene: F8 (HGNC:3546)
Evidence Code: PM5 — Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Example: Arg156His is pathogenic; now you observe Arg156Cys.
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Gene: F8 (HGNC:3546)
Evidence Code: PM5 — Moderate
Modification Type: Gene-specific
This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on the 
F8
 rule specifications from the Coagulation Factor Deficiency VCEP and where 
in silico
 predictors do not suggest a splicing defect.
Gene: F8 (HGNC:3546)
Evidence Code: PM5 — Supporting
Modification Type: Gene-specific
This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on the 
F8
 rule specifications from the Coagulation Factor Deficiency VCEP and where 
in silico
 predictors do not suggest a splicing defect.
Gene: F8 (HGNC:3546)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: F8 (HGNC:3546)
Evidence Code: PP1 — Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Note: May be used as stronger evidence with increasing segregation data.
Gene: F8 (HGNC:3546)
Evidence Code: PP1 — Strong
Modification Type: Disease-specific
The code is application when there are ≥4 meioses across ≥2 families.
Gene: F8 (HGNC:3546)
Evidence Code: PP1 — Moderate
Modification Type: Disease-specific
The code is application when there are at least 3 meioses across one or more families.
Gene: F8 (HGNC:3546)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific
The code is application when there are 2 meioses in one family 
OR
 1 meiosis between 2 affected siblings.
Gene: F8 (HGNC:3546)
Evidence Code: PP2 — Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Gene: F8 (HGNC:3546)
Evidence Code: PP3 — Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the 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 should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
Gene: F8 (HGNC:3546)
Evidence Code: PP3 — Supporting
Modification Type: Gene-specific
Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.5.
Gene: F8 (HGNC:3546)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: F8 (HGNC:3546)
Evidence Code: PP4 — Moderate
Modification Type: Disease-specific
Proband must meet hemophilia A phenotype criteria AND have full gene sequencing and deletion/duplication analysis.
Gene: F8 (HGNC:3546)
Evidence Code: PP5 — Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: F8 (HGNC:3546)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: F8 (HGNC:3546)
Evidence Code: BA1 — Stand Alone
Modification Type: Gene-specific
MAF cutoff of greater or equal to 0.0333% (or 0.000333).
Gene: F8 (HGNC:3546)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: F8 (HGNC:3546)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
MAF cutoff of greater than or equal to 0.00333% (or 0.0000333).
Gene: F8 (HGNC:3546)
Evidence Code: BS2 — Original ACMG Summary
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Gene: F8 (HGNC:3546)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
This evidence code can be used when a 
F8
 variant is observed in a male with a normal factor VIII activity level (<40% IU) using a one stage and/or a chromogenic assay.
Gene: F8 (HGNC:3546)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: F8 (HGNC:3546)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific
This code can be used for 
F8
 gene variants studied in a cell line or mouse model setting that confer a normal factor VIII activity level AND normal factor VIII antigen level OR normal Western Blot.
Gene: F8 (HGNC:3546)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific
This code can be used for 
F8
 gene variants studied in a cell line or mouse model setting that confer the following results:                    




Normal factor VIII activity level, OR


Abnormal factor VIII activity level with abnormal 2N binding assay suggesting a diagnosis of VWD Normandy (VWD 2N) instead of hemophilia A.
Gene: F8 (HGNC:3546)
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: F8 (HGNC:3546)
Evidence Code: BS4 — Strong
Modification Type: Disease-specific
This evidence code can be used when a 
F8
 variant is observed in a male with a family history of hemophilia A and has a normal factor VIII activity level.
Gene: F8 (HGNC:3546)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: F8 (HGNC:3546)
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: F8 (HGNC:3546)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: F8 (HGNC:3546)
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: F8 (HGNC:3546)
Evidence Code: BP4 — Supporting
Modification Type: Gene-specific
This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.05.
Gene: F8 (HGNC:3546)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: F8 (HGNC:3546)
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: F8 (HGNC:3546)
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: F8 (HGNC:3546)
Evidence Code: BP7 — Supporting
Modification Type: Gene-specific
Splice AI should be used to suggest no splicing impact. Splicing prediction score of less than or equal to 0.05 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5).