owencqueen/cgbench_data huggingface dataset:
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PVS1 — Very Strong
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)).
Gene: JAK3 (HGNC:6193)
Evidence Code: PVS1 — Strong
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:




For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 24, or variants in the last 50 nucleotides of the penultimate exon after c.3157, codon 1053, in exon 23), at least one pathogenic variant 
must be
 present downstream in order to apply PVS1_Strong.
Gene: JAK3 (HGNC:6193)
Evidence Code: PVS1 — Moderate
Modification Type: General recommendation
Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:




For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 24, or variants in the last 50 nucleotides of the penultimate exon after c.3157, codon 1053, in exon 23), when at least one pathogenic variant is 
not
 present downstream downgrade to PVS1_Moderate.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PS1 — Strong
Modification Type: Gene-specific
It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.


Applicable if the previously established variant is classified as 
pathogenic
 by SCID VCEP specifications for 
JAK3.
Gene: JAK3 (HGNC:6193)
Evidence Code: PS1 — Moderate
Modification Type: Gene-specific,Strength
It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T


Applicable if the previously established variant is classified as 
likely pathogenic
 by SCID VCEP specifications for 
JAK3.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PS2 — Very Strong
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: JAK3 (HGNC:6193)
Evidence Code: PS2 — Strong
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: JAK3 (HGNC:6193)
Evidence Code: PS2 — Moderate
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: JAK3 (HGNC:6193)
Evidence Code: PS2 — Supporting
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PS3 — Strong
Modification Type: Gene-specific
PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the JAK3-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level.
Gene: JAK3 (HGNC:6193)
Evidence Code: PS3 — Supporting
Modification Type: Gene-specific,Strength
PS3_Supporting can be applied based on an abnormal result in an 
in vitro
 kinase activity assay.




Approved assay instance: Roberts et al., 2004 (PMID: 14615376).




At least one previously observed proband with the JAK3 variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific
Defined to include missense alterations of two JH2 domain residues: R651W and C759R (PMID: 11668610).
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PM2 — Supporting
Modification Type: Gene-specific
gnomAD popmax filtering allele frequency  <0.000115




An additional requirement is that 
no homozygotes
 have been observed in gnomAD.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PM3 — Very Strong
Modification Type: General recommendation
Use ClinGen SVI recommendations for 
in trans
 criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
JAK3.
Gene: JAK3 (HGNC:6193)
Evidence Code: PM3 — Strong
Modification Type: General recommendation
Use ClinGen SVI recommendations for 
in trans
 criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
JAK3.
Gene: JAK3 (HGNC:6193)
Evidence Code: PM3 — Moderate
Modification Type: General recommendation
Use ClinGen SVI recommendations for 
in trans
 criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
JAK3.
Gene: JAK3 (HGNC:6193)
Evidence Code: PM3 — Supporting
Modification Type: General recommendation
Use ClinGen SVI recommendations for 
in trans
 criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
JAK3.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PM4 — Moderate
Modification Type: Gene-specific
When applied to deletion variants, the deleted region must contain a known 
pathogenic
 or 
likely pathogenic
 variant that is not predicted/observed to alter splicing.
Gene: JAK3 (HGNC:6193)
Evidence Code: PM4 — Supporting
Modification Type: Gene-specific,Strength
When applied to deletion variants, the deleted region must contain a known 
VUS
 variant that is not predicted/observed to alter splicing.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PM5 — Moderate
Modification Type: Gene-specific
Applicable if a previously established variant is classified as 
pathogenic
 by SCID VCEP specifications for 
JAK3.
 Previously established variant must be classified by SCID VCEP specifications for 
JAK3.
Gene: JAK3 (HGNC:6193)
Evidence Code: PM5 — Supporting
Modification Type: Gene-specific,Strength
Applicable if a previously established variant is classified as 
likely pathogenic
 by SCID VCEP specifications for 
JAK3.
 Previously established variant must be classified by SCID VCEP specifications for 
JAK3.
Gene: JAK3 (HGNC:6193)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: JAK3 (HGNC:6193)
Evidence Code: PM6 — Strong
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: JAK3 (HGNC:6193)
Evidence Code: PM6 — Moderate
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: JAK3 (HGNC:6193)
Evidence Code: PM6 — Supporting
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PP1 — Strong
Modification Type: General recommendation
Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.
Gene: JAK3 (HGNC:6193)
Evidence Code: PP1 — Moderate
Modification Type: General recommendation
Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.
Gene: JAK3 (HGNC:6193)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation
Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation
Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.


Do not apply to missense variants.
Gene: JAK3 (HGNC:6193)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: JAK3 (HGNC:6193)
Evidence Code: PP4 — Strong
Modification Type: Disease-specific,Gene-specific
A patient score of ≥ 6 points
1
. 


1
CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).
Gene: JAK3 (HGNC:6193)
Evidence Code: PP4 — Moderate
Modification Type: Disease-specific,Gene-specific
A patient score of 2-<6 points (see instructions below).
Gene: JAK3 (HGNC:6193)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific,Gene-specific
A patient score of 1-<2 points (see instructions below).
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: JAK3 (HGNC:6193)
Evidence Code: BA1 — Stand Alone
Modification Type: Gene-specific
gnomAD popmax filtering allele frequency >0.00447
Gene: JAK3 (HGNC:6193)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: JAK3 (HGNC:6193)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
gnomAD popmax filtering allele frequency >0.00100
1


1
Consider also bottleneck populations.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: BS2 — Supporting
Modification Type: Strength
Only to be used when the variant is observed in the homozygous state in a healthy adult.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: BS4 — Strong
Modification Type: General recommendation,None
Can be applied without additional specifications.
Gene: JAK3 (HGNC:6193)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
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: JAK3 (HGNC:6193)
Evidence Code: BP7 — Supporting
Modification Type: Disease-specific
Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.


The variant should be predicted not to impact splicing by at least two out of three 
in silico
 tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).


Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is not required in order to apply BP7.