Table 2. In silico tools with pairs of non-overlapping thresholds that reach at least supporting evidence strength for both pathogenic and benign prediction.

LR: likelihood ratio; CI: confidence interval; PV: predicted variants.

	Pathogenic prediction					Benign Prediction
Tool	Pathogenic threshold	Sensitivity	LR+	LR+ 95% CI	Strength (pathogenic)	Benign threshold	Specificity	LR-	LR- 95% CI	Strength (benign)	Correctly PV	% of correctly PV
All SNVs
BayesDel_addAF	≥0.39	0.6	3.21	[2.19, 4.72]	Supporting	<0.23	0.44	0.35	[0.26, 0.47]	Supporting	302	56.87
CADD	>25	0.39	8.27	[4.34, 15.75]	Moderate	≤21.75	0.78	0.42	[0.37, 0.48]	Supporting	418	47.18
CADD	>16.3	0.82	2.59	[2.1, 3.2]	Supporting	≤16.3	0.68	0.26	[0.21, 0.31]	Supporting	703	79.35
Eigen-PC	>1.9	0.79	3	[2.21, 4.07]	Supporting	≤1.9	0.74	0.28	[0.22, 0.35]	Supporting	415	78.15
GERP++	>4.22	0.44	4.33	[2.51, 7.49]	Supporting	≤0.15	0.35	0.32	[0.22, 0.46]	Supporting	225	42.37
MetaSVM	>0.81	0.55	3.25	[2.16, 4.89]	Supporting	≤0.46	0.6	0.38	[0.3, 0.48]	Supporting	272	56.55
phyloP100way	>7.32	0.15	17.8	[2.5, 127]	Supporting	≤0.8	0.57	0.36	[0.28, 0.46]	Supporting	130	24.48
REVEL	>0.77	0.63	3.05	[2.12, 4.4]	Supporting	≤0.7	0.69	0.38	[0.31, 0.47]	Supporting	309	64.24
SpliceAI	>0.3	0.67	58.12	[27.23, 124.03]	Strong	≤0.3	0.99	0.33	[0.23, 0.48]	Supporting	637	96.08
Missense only
BayesDel_addAF	≥0.41	0.54	3.35	[2.2, 5.12]	Supporting	<0.22	0.44	0.32	[0.23, 0.45]	Supporting	241	51.72
CADD	>23.25	0.6	3.19	[2.17, 4.69]	Supporting	≤20.9	0.62	0.36	[0.28, 0.46]	Supporting	283	60.6
Eigen-PC	>1.9	0.78	2.93	[2.16, 3.98]	Supporting	≤1.9	0.74	0.3	[0.24, 0.38]	Supporting	357	76.61
GERP++	>4.22	0.44	4.27	[2.47, 7.4]	Supporting	≤–0.87	0.29	0.31	[0.2, 0.47]	Supporting	187	40.13
MetaSVM	>0.8	0.58	3.08	[2.09, 4.53]	Supporting	≤0.39	0.56	0.37	[0.29, 0.48]	Supporting	267	57.3
phastCons30way	>0.94	0.52	3.19	[2.09, 4.88]	Supporting	≤0.41	0.61	0.36	[0.28, 0.46]	Supporting	252	54.08
phyloP100way	>7.32	0.16	19.11	[2.68, 136.47]	Supporting	≤0.56	0.53	0.35	[0.27, 0.46]	Supporting	119	25.54
REVEL	>0.77	0.62	3.02	[2.09, 4.35]	Supporting	≤0.7	0.69	0.39	[0.32, 0.48]	Supporting	297	63.73
Non-missense only
CADD	>11.5	0.93	8.62	[3.42, 21.77]	Supporting	≤11.5	0.89	0.08	[0.05, 0.11]	Supporting	350	92.84
SNVs in HBB
BayesDel_addAF	≥0.31	0.8	6.43	[2.23, 18.58]	Supporting	<0.31	0.88	0.22	[0.17, 0.3]	Supporting	210	81.08
CADD	>25.25	0.42	31.64	[4.5, 222.38]	Moderate	≤22.65	0.92	0.42	[0.37, 0.48]	Supporting	264	48.71
CADD	>10.8	0.94	3.26	[2.29, 4.64]	Supporting	≤10.8	0.71	0.08	[0.05, 0.12]	Supporting	494	91.14
SNVs in HBA1
CADD	>22.95	0.59	4.94	[2.29, 10.68]	Supporting	≤17	0.66	0.3	[0.19, 0.48]	Supporting	84	61.76