owencqueen/cgbench_data huggingface dataset:
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
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)) with one specification:




PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay but removing/altering the critical forkhead domain (amino acids 270-367; Newman et al., 2020; PMID: 31914405) based on recommendations from Walker et. al., 2023 (PMID: 37352859).
Gene: FOXN1 (HGNC:12765)
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 two specifications:




For variants not predicted to undergo nonsense-mediated decay, but removing >10% of protein, (i.e. variants in the last exon, exon 9, or variants in the last 50 nucleotides of the penultimate exon after c.1577, codon 526, in exon 8), at least one pathogenic variant must be present downstream in order to apply PVS1_Strong


PVS1_Strong can be applied to variants not predicted to undergo nonsense-mediated decay but removing/altering the transactivation domain (amino acids 511-563; Schlake et al., 2000 PMID: 10767081).
Gene: FOXN1 (HGNC:12765)
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 9, or variants in the last 50 nucleotides of the penultimate exon after c.1577, codon 526, in exon 8), when at least one pathogenic variant is not present downstream downgrade to PVS1_Moderate
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PS1 — Strong
Modification Type: Gene-specific
Applicable for a same amino acid change if previously established variant is classified as pathogenic by SCID VCEP specifications for 
FOXN1.


Can also be applied for variants with the same predicted splicing event as a known Pathogenic variant (as classified by the SCID VCEP specifications for 
FOXN1
), only when the strength of the prediction for the variant under assessment is of similar or higher strength than the strength of the prediction for the comparison (Likely) Pathogenic variant (i.e., per in silico splicing tool SpliceAI). See attached instructions (from Table 2 of PMID: 
37352859
) for determining when PS1 should be applied at PS1_Strong, _Moderate, or _Supporting.
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS1 — Moderate
Modification Type: Gene-specific,Strength
Applicable for a same amino acid change if previously established variant is classified as likely pathogenic by SCID VCEP specifications for 
FOXN1.


Can also be applied for variants with the same predicted splicing event as a known (Likely) Pathogenic variant (as classified by the SCID VCEP specifications for 
FOXN1
), only when the strength of the prediction for the variant under assessment is of similar or higher strength than the strength of the prediction for the comparison (Likely) Pathogenic variant (i.e., per in silico splicing tool SpliceAI). See attached instructions (from Table 2 of PMID: 
37352859
) for determining when PS1 should be applied at PS1_Strong, _Moderate, or _Supporting.
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS1 — Supporting
Modification Type: Gene-specific,Strength
Can be applied for variants with the same predicted splicing event as a known (Likely) Pathogenic variant (as classified by the SCID VCEP specifications for 
FOXN1
), only when the strength of the prediction for the variant under assessment is of similar or higher strength than the strength of the prediction for the comparison (Likely) Pathogenic variant (i.e., per in silico splicing tool SpliceAI). See attached instructions (from Table 2 of PMID: 
37352859
) for determining when PS1 should be applied at PS1_Strong, _Moderate, or _Supporting.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PS2 — Very Strong
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS2 — Strong
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS2 — Moderate
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS2 — Supporting
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PS3 — Strong
Modification Type: Gene-specific
PS3 may be applied at the strong level for evidence from an animal model expressing the variant of interest and recapitulating FOXN1 deficiency (i.e. a mouse model with T cell lymphopenia).
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS3 — Moderate
Modification Type: Gene-specific,Strength
PS3 may be applied at the moderate level based on a luciferase assay showing reduced (<50%) activity, as part of a validated assay with pathogenic and benign controls (PMID: 37419334).
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS3 — Supporting
Modification Type: Gene-specific,Strength
PS3 may be applied at the supporting level based on a luciferase assay, without sufficient validation controls, showing reduced (<50%) activity, such as those reported in PMIDs: 31566583, 33464451, 34860543.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PS4 — Very Strong
Modification Type: Disease-specific
Sum of case scores ≥8 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific
Sum of case scores 4-7.75 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific
Sum of case scores 2-3.75 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific
Sum of case scores 1-1.75 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific
Applicable for variants in the DNA binding forkhead domain (amino acids 270-367), which is a well-established functional domain (Newman et al., 2020; PMID: 31914405) of 
FOXN1
 with low tolerance for benign variation.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PM2 — Supporting
Modification Type: Gene-specific
gnomAD Grpmax filtering allele frequency ≤0.00002412
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PM3 — Very Strong
Modification Type: General recommendation
Sum of case scores ≥8 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
Evidence Code: PM3 — Strong
Modification Type: General recommendation
Sum of case scores 4-7.75 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
Evidence Code: PM3 — Moderate
Modification Type: General recommendation
Sum of case scores 2-3.75 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
Evidence Code: PM3 — Supporting
Modification Type: General recommendation
Sum of case scores 1-1.75 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PM4 — Moderate
Modification Type: Gene-specific
Additional requirement that 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: FOXN1 (HGNC:12765)
Evidence Code: PM4 — Supporting
Modification Type: Gene-specific,Strength
Additional requirement that when applied to deletion variants, the deleted region must contain a known VUS variant that is not predicted/observed to alter splicing.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PM5 — Moderate
Modification Type: Gene-specific
Applicable if previously established variant is classified as pathogenic by SCID VCEP specifications for 
FOXN1.
 Previously established variant must be classified by SCID VCEP specifications for 
FOXN1.
Gene: FOXN1 (HGNC:12765)
Evidence Code: PM5 — Supporting
Modification Type: Gene-specific,Strength
Applicable if previously established variant is classified as likely pathogenic by SCID VCEP specifications for 
FOXN1.
 Previously established variant must be classified by SCID VCEP specifications for 
FOXN1.
Gene: FOXN1 (HGNC:12765)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: FOXN1 (HGNC:12765)
Evidence Code: PM6 — Strong
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: FOXN1 (HGNC:12765)
Evidence Code: PM6 — Moderate
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: FOXN1 (HGNC:12765)
Evidence Code: PM6 — Supporting
Modification Type: General recommendation,Gene-specific
Use ClinGen SVI recommendations for 
de novo
 criteria (see instructions below).
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PP1 — Strong
Modification Type: General recommendation
Can be applied when there is a 32:1 likelihood ratio (LOD score ≥1.5, summed across all families with segregation evidence) per recommendations from PMID: 30311386 Table 4a. See instructions for calculating the estimated LOD score.
Gene: FOXN1 (HGNC:12765)
Evidence Code: PP1 — Moderate
Modification Type: General recommendation
Can be applied when there is a 16:1 likelihood ratio (LOD score 1.2-<1.5, summed across all families with segregation evidence) per recommendations from PMID: 30311386 Table 4a. See instructions for calculating the estimated LOD score.
Gene: FOXN1 (HGNC:12765)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation
Can be applied when there is a 4:1 likelihood ratio (LOD score 0.6-<1.2, summed across all families with segregation evidence) per recommendations from PMID: 30311386 Table 4a. See instructions for calculating the estimated LOD score.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: PP3 — Moderate
Modification Type: General recommendation
Moderate evidence can be applied for a REVEL score of ≥0.932, downgraded from the recommendation of Strong in Pejaver et al., 2022 (PMID: 36413997).
Gene: FOXN1 (HGNC:12765)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation
Supporting evidence can be applied for a REVEL score of ≥0.644 (to <0.932), based on recommendations of Pejaver et al., 2022 (PMID: 36413997).


Also applicable to missense, synonymous, or intronic variants predicted to impact splicing by SpliceAI ∆ score ≥0.2
Gene: FOXN1 (HGNC:12765)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: FOXN1 (HGNC:12765)
Evidence Code: PP4 — Moderate
Modification Type: Disease-specific,Gene-specific
Patient score of ≥2 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific,Gene-specific
Patient score of 1-<2 points (see instructions below)
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: FOXN1 (HGNC:12765)
Evidence Code: BA1 — Stand Alone
Modification Type: Gene-specific
gnomAD Grpmax filtering allele frequency >0.00447
Gene: FOXN1 (HGNC:12765)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: FOXN1 (HGNC:12765)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
gnomAD Grpmax filtering allele frequency >0.00141 OR a bottle-necked population with a MAF >0.00141 may be used for this criterion. Caveat: If the variant is known to be a founder variant in the bottle-necked population do not consider the frequency in that population for BS1.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: BS4 — Strong
Modification Type: None
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: FOXN1 (HGNC:12765)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
Applicable only when observed in cis with a pathogenic variant in any inheritance pattern, with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
FOXN1.
Gene: FOXN1 (HGNC:12765)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: BP4 — Supporting
Modification Type: General recommendation
•Supporting evidence can be applied for a REVEL score of <0.290 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).


•Also applicable to synonymous or intronic variants not predicted to impact splicing by SpliceAI ∆ score ≤0.1
Gene: FOXN1 (HGNC:12765)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: FOXN1 (HGNC:12765)
Evidence Code: BP5 — Supporting
Modification Type: None
Use with no specification.
Gene: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
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: FOXN1 (HGNC:12765)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
A synonymous variant, or deep intronic variant affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions, for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site (SpliceAI ∆ score ≤0.1) AND the nucleotide is not highly conserved.