owencqueen/cgbench_data huggingface dataset:
Gene: TCF4 (HGNC:11634)
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 up to p.E643 which corresponds to the distal most de novo truncating variant in an affected patient reported to date.
1


PVS1 can be applied for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).
Gene: TCF4 (HGNC:11634)
Evidence Code: PVS1 — Supporting
Modification Type: Disease-specific
Null variant in a gene where loss of function is a known mechanism of disease.




PVS1_Supporting is applicable for initiation codon variants in 
TCF4.
Gene: TCF4 (HGNC:11634)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
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: TCF4 (HGNC:11634)
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: TCF4 (HGNC:11634)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Located in a mutational hot spot and/or critical and well-established functional domain.




Basic Helix-Loop-Helix domain (bHLH): aa 564-617
3
,
2
Gene: TCF4 (HGNC:11634)
Evidence Code: PM4 — Moderate
Modification Type: None
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: TCF4 (HGNC:11634)
Evidence Code: PM5 — Moderate
Modification Type: None
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.




A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.
Gene: TCF4 (HGNC:11634)
Evidence Code: PM6 — Very Strong
Modification Type: Strength
Confirmed de novo without confirmation of paternity and maternity.




≥4 independent occurrences of PM6.
Gene: TCF4 (HGNC:11634)
Evidence Code: PM6 — Strong
Modification Type: Strength
Confirmed de novo without confirmation of paternity and maternity.




≥2 independent occurrences of PM6.
Gene: TCF4 (HGNC:11634)
Evidence Code: PM6 — Moderate
Modification Type: No change
Confirmed de novo without confirmation of paternity and maternity.
Gene: TCF4 (HGNC:11634)
Evidence Code: PP1 — Strong
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




≥5 informative meiosis
Gene: TCF4 (HGNC:11634)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




3-4 informative meiosis
Gene: TCF4 (HGNC:11634)
Evidence Code: PP1 — Supporting
Modification Type: Strength
Co-segregation with disease in multiple affected family members.




2 informative meiosis
Gene: TCF4 (HGNC:11634)
Evidence Code: PP3 — Supporting
Modification Type: Clarification
Multiple lines of computational evidence support a deleterious effect on the gene or gene product.




For missense variants use REVEL with a score ≥ 0.75.


For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).
Gene: TCF4 (HGNC:11634)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Allele frequency greater than expected for disease.




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: TCF4 (HGNC:11634)
Evidence Code: BS2 — Strong
Modification Type: Strength
Observed in the heterozygous/hemizygous state in a healthy adult.




2 unaffected (related or unrelated) heterozygotes
Gene: TCF4 (HGNC:11634)
Evidence Code: BS2 — Supporting
Modification Type: Strength
Observed in the heterozygous/hemizygous state in a healthy adult.




1 unaffected (related or unrelated) heterozygote
Gene: TCF4 (HGNC:11634)
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


Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.
Gene: TCF4 (HGNC:11634)
Evidence Code: BS4 — Supporting
Modification Type: Strength
Lack of segregation in affected members of a family.




Absent in a similarly affected family member
Gene: TCF4 (HGNC:11634)
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.




Applicable for 
TCF4
 for 
in trans
 state
Gene: TCF4 (HGNC:11634)
Evidence Code: BP5 — Supporting
Modification Type: Disease-specific
Variant found in a case with an alternate molecular basis for disease.