owencqueen/cgbench_data huggingface dataset:
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PVS1 — Very Strong
Modification Type: Gene-specific,Strength
Use ACVRL1 PVS1 Decision Tree (see attachments)
Gene: ACVRL1 (HGNC:175)
Evidence Code: PVS1 — Strong
Modification Type: Gene-specific,Strength
Use ACVRL1 PVS1 Decision Tree (see attachments)
Gene: ACVRL1 (HGNC:175)
Evidence Code: PVS1 — Moderate
Modification Type: Gene-specific,Strength
Use ACVRL1 PVS1 Decision Tree (see attachments)
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PS1 — Strong
Modification Type: No change
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: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PS2 — Strong
Modification Type: Clarification,Disease-specific
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: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific,Strength
mRNA splicing assays can be used as strong functional evidence. 


Note:
 level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact.
Gene: ACVRL1 (HGNC:175)
Evidence Code: PS3 — Moderate
Modification Type: Disease-specific,Strength
See PS3_Supporting and Instructions below.
Gene: ACVRL1 (HGNC:175)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific,Strength
Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2


Note:
 Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn.






Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling


Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)


Subcellular protein localization


Morphology: Morphology & actin cytoskeleton, tubulogenesis


Somatic variant 2
nd
 hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786).
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific
4+ probands with phenotype consistent with HHT.
Gene: ACVRL1 (HGNC:175)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific
2-3 probands with phenotype consistent with HHT.
Gene: ACVRL1 (HGNC:175)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific
1 proband with phenotype consistent with HHT.
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific
Apply if variant is located in a critical residue:




ACVRL1
:


glycine-rich loop: G209-V216


phosphate anchor: K229


C-helix E pairing the phosphate anchor: E242


catalytic loop: R329-N335


metal-binding loop: D348-L351


BMP10
 interaction cluster


(Cys46, Cys51, Val56, Arg61, His66, Asn71, Leu76, Pro81, Asn86, Asp91)
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,Strength
<6 total alleles in gnomAD or <0.00004 (0.004%) in gnomAD subpopulations.
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PM5 — Strong
Modification Type: Disease-specific,Strength
≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.
Gene: ACVRL1 (HGNC:175)
Evidence Code: PM5 — Moderate
Modification Type: Disease-specific,Strength
A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.
Gene: ACVRL1 (HGNC:175)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PP1 — Strong
Modification Type: Disease-specific,Strength
5+ meioses (1/32 likelihood)
Gene: ACVRL1 (HGNC:175)
Evidence Code: PP1 — Moderate
Modification Type: Disease-specific,Strength
4 meioses (1/16 likelihood)
Gene: ACVRL1 (HGNC:175)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific,Strength
3 meioses (1/8 likelihood)
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: PP3 — Supporting
Modification Type: Disease-specific
For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2.


For synonymous and intronic variants: SpliceAI score ≥0.2.
Gene: ACVRL1 (HGNC:175)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: ACVRL1 (HGNC:175)
Evidence Code: PP4 — Moderate
Modification Type: Disease-specific,Strength
Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both 
ENG
 and 
ACVRL1
 with any other identified variants ruled out.
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: ACVRL1 (HGNC:175)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF.
Gene: ACVRL1 (HGNC:175)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: ACVRL1 (HGNC:175)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific,Strength
>0.2% to <1% in general population databases (e.g. gnomAD) based on Popmax FAF, 
or
 if variant meets BS1_Supporting and has ≥2 homozygotes.
Gene: ACVRL1 (HGNC:175)
Evidence Code: BS1 — Supporting
Modification Type: Disease-specific,Strength
>0.08% to 0.2% (based on gnomAD Popmax FAF).
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific,Strength
mRNA splicing assays 


Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling


Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)


Subcellular protein localization


Morphology: Morphology & actin cytoskeleton, tubulogenesis
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: BS4 — Strong
Modification Type: Clarification,Disease-specific
Lack of segregation in affected members of a family.
Gene: ACVRL1 (HGNC:175)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules.
Gene: ACVRL1 (HGNC:175)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1.


For synonymous and intronic variants: SpliceAI score ≤0.1.
Gene: ACVRL1 (HGNC:175)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: ACVRL1 (HGNC:175)
Evidence Code: BP5 — Supporting
Modification Type: Disease-specific
Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in 
ENG
.
Gene: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
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: ACVRL1 (HGNC:175)
Evidence Code: BP7 — Supporting
Modification Type: Disease-specific
A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence.