owencqueen/cgbench_data huggingface dataset:
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PVS1 — Very Strong
Modification Type: Gene-specific
Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PVS1 — Strong
Modification Type: Gene-specific,Strength
Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PVS1 — Moderate
Modification Type: Disease-specific,Strength
Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PS1 — Strong
Modification Type: None
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PS1 — Moderate
Modification Type: Strength
Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific,Strength
Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.
Moderate = 1.0 points total.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PS2 — Supporting
Modification Type: Disease-specific,Strength
Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.
Supporting = 0.5 points total.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PS3 — Strong
Modification Type: Gene-specific
Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets PVS1. If variant meets PVS1_strong, either apply PS3_moderate or upgrade to PVS1.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PS3 — Moderate
Modification Type: Gene-specific,Strength
Transactivation assays demonstrating altered transactivation (<20% of wt and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) OR ≥ 2 secondary assays demonstrating altered function.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PS3 — Supporting
Modification Type: Gene-specific,Strength
Transactivation assays demonstrating enhanced transactivation (>115% of wt).
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific
≥ 4 probands meeting at least one of the RUNX1-phenotypic criteria.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific,Strength
2-3 probands meeting at least one of the RUNX1-phenotypic criteria.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific,Strength
1 proband meeting at least one of the RUNX1-phenotypic criteria.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PM1 — Moderate
Modification Type: Gene-Specific
Variant affecting one of the following amino acid residues within he RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PM1 — Supporting
Modification Type: Gene-specific,Strength
Variant affecting one of the other amino acid residues 89-204 within the RHD.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PM2 — Supporting
Modification Type: Strength
Variant must be completely absent from all population databases.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PM4 — Moderate
Modification Type: Gene-specific
In-frame deletion/insertion impacting at least one of the following amino acid residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PM4 — Supporting
Modification Type: Gene-specific,Strength
In-frame deletion/insertion impacting at least one of the other amino acid residues 89-204 within the RHD.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PM5 — Strong
Modification Type: Strength
Missense change at an AA residue where ≥ 2 different missense changes which have been determined to be pathogenic before. Not applicable in combination with PM1.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PM5 — Moderate
Modification Type: None
Missense change at an amino acid residue where a different missense change which has been determined to be pathogenic before.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PM5 — Supporting
Modification Type: Strength
Missense change at an amino acid residue where a different missense change which has been determined to be likely pathogenic before. PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4).
Gene: RUNX1 (HGNC:10471)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PM6 — Moderate
Modification Type: Disease-specific,Strength
Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.
Moderate = 1.0 points total.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PP1 — Strong
Modification Type: Disease-specific,Strength
≥ 7 meioses observed within one or across multiple families.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PP1 — Moderate
Modification Type: Disease-specific,Strength
Co-segregation with disease in multiple affected family members. 5 or 6 meioses observed within one or across multiple families.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific
3 or 4 meioses observed within one or across multiple families.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: PP3 — Supporting
Modification Type: Gene-specific,Disease-specific
For missense variants: REVEL score ≥ 0.88.
For missense, synonymous and intronic (intron 4-8) variants: SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites.
Gene: RUNX1 (HGNC:10471)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: RUNX1 (HGNC:10471)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: RUNX1 (HGNC:10471)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Minor allele frequency between 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.
Gene: RUNX1 (HGNC:10471)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: BS3 — Strong
Modification Type: Gene-specific
Transactivation assays demonstrating normal transactivation (80- 115% of wt) AND data from a secondary assay demonstrating normal function.
Gene: RUNX1 (HGNC:10471)
Evidence Code: BS3 — Supporting
Modification Type: Gene-specific,Strength
Transactivation assays demonstrating normal transactivation (80- 115% of wt).
Gene: RUNX1 (HGNC:10471)
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: RUNX1 (HGNC:10471)
Evidence Code: BS4 — Strong
Modification Type: General recommendation
Applied when seen in ≥ 2 informative meioses.
Gene: RUNX1 (HGNC:10471)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: RUNX1 (HGNC:10471)
Evidence Code: BP2 — Supporting
Modification Type: None
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: RUNX1 (HGNC:10471)
Evidence Code: BP4 — Supporting
Modification Type: Gene-specific,Disease-specific
For missense variants: REVEL score <0.50 AND SpliceAI ≤ 0.20.
For synonymous and Intronic variants: SpliceAI ≤ 0.20.
Gene: RUNX1 (HGNC:10471)
Evidence Code: BP7 — Supporting
Modification Type: Gene-specific,Disease-specific
BP7 is applicable for synonymous and intronic which SpliceAI ≤ 0.20 AND evolutionary conservation prediction algorithms predict the site as not conserved phyloP100 way (GRCh38/hg38) ≤2.0).