Table 1:

Overview of association analysis models.

Models	Primary models				Secondary models
	Control	Ultra-rare functional variants			Rare functional variants		Loss of Function variants
	Synonymous	PPh2	REVEL	MTR	Rare variants + URVs	Rare variants − URVs	Rare variants + URVs	Rare variants − URVs	URVs only
Minor Allele Frequencies
Internal MAF	<0.0005	<0.0005	<0.0005	<0.0005	<0.001	without URVs	<0.001	without URVs	<0.0005
DiscovEHR MAF	0	0	0	0	<0.001		<0.001		0
gnomAD r2 MAF	0	0	0	0	<0.001		<0.001		0
Classes of Variants
ClinEff Effects	Synonymous	Functional	Functional	Functional	Functional	Functional	pLoF	pLoF	pLoF
Missense variants filters
PPh2 prediction	-	"Probably"	-	-	"Probably"	"Probably"	-	-	-
REVEL score	-	-	≥ 0.5	≥ 0.5	-	-	-	-	-
MTR score	-	-	-	≤ 0.78	-	-	-	-	-

MAF: Minor Allele Frequency. PPh2: Polyphen 2 Human Diversity based prediction. REVEL: Rare Exome Variant Ensemble Learner. MTR: Missense Tolerance Ratio score. pLoF: predicted loss-of-function variants. pLoF variants included stop-gain & stop-loss variants, frameshift insertions & deletions, and canonical splice-site variants. Functional variants included pLoF, in-frame insertions & deletions, and missense variants (the missense variants were filtered using PPh2, REVEL, and MTR predictions as indicated). MAF from gnomAD were based on the ‘genomes’ subset. The cut-offs for REVEL & MTR scores were based on Ref.⁸