Table 3.

Cases with pathogenic or likely pathogenic variants identified by targeted gene sequencing

ID	Variant	Allele frequency		In silico prediction				Previous report [ref.]	ACMG-AMP classification
		gnomADa	ABraOM	SIFTb	PP2c	GERP++d	CADDpe
4	AXIN1 p.(Ala311Thr)	0.0000	0.0000	T	D	5.25	28.4	No	NA (GUS)
	COL1A2 p.(Arg708Gln)	0.0012 (LAT)	0.0016	D	D	5.84	25.1	[40, 48-52]	Pathogenic (II): PS1, PS3, PP3
	FOXC2 p.(Cys498Arg)	0.0034 (ASJ)	0.0008	T	D	4.88	15.5	No	NA (GUS)
	PTDSS2 p.(Val250Met)	0.0060 (ASJ)	0.0041	D	D	4.50	22	No	NA (GUS)
8	NOTCH2 p.(Leu2408His)	0.0032 (NFE)	0.0074	D	D	5.35	25.5	ClinVar	VUS
	PLS3 p.(Leu603Phe)	0.0000	0.0000	D	D	5.59	15.6	No	VUS
	WNT1 p.(Gly169Asp)	0.0009 (AFR)	0.0000	D	D	4.94	35	[39]	Likely pathogenic (III): PS1, PP1, PP2, PP3
F4	IDUA p.(His82Gln)	0.0047 (NFE)	0.0082	T	D	–0.41	9.9	[41, 53, 54]	Likely pathogenic (II): PS3, PM5
	KCNMA1 p.(Arg813Gln)	< 0.0001 (NFE)	0.0000	D	D	4.73	26.9	No	NA (GUS)

Abbreviations: ACMG-AMP, American College of Medical Genetics and Genomics and the Association for Molecular Pathology; CADD, combined annotation–dependent depletion; GERP, genome evolutionary rate profiling; GUS, genes of uncertain significance; ID, identification; SIFT, Sorting Intolerant From Tolerant; VUS, variants of uncertain significance.

^aHighest ethnicity-specific minor allele frequencies are reported (AFR, African; ASJ, Ashkenazi Jewish; LAT, Latino; NFE, Non-Finnish European).

^bSIFT output prediction: D, damaging; T, tolerated.

^cPolyPhen2 HumDiv prediction: B, benign; D, probably damaging; P, possibly damaging.

^dGERP++ rejected substitutions (RS) score (a suggested threshold for deleteriousness is > 4.4).

^ePHRED-like scaled C-score according to the CADD framework (a suggested threshold for deleteriousness is > 15); ABraOM, Online Archive of Brazilian Mutations; gnomAD, Genome Aggregation Database; NA, not applicable.