Table 1.

List of the Germline CDC42 Missense Mutations Identified in This Study

Exon	Nucleotide Change	Amino Acid Change	Domain	Mutation Group	Subjects	Origin	MetaSVMa	CADD phreda	REVELa	ACMG
1	c.62T>C	p.Ile21Thr	α1	III	1	de novo	0.3729	27.1	0.901	pathogenic
1	c.68A>G	p.Tyr23Cys	α1	III	2	de novo	0.7752	27.1	0.937	pathogenic
3	c.191A>G	p.Tyr64Cys	switch II	I	3	de novo	0.7976	23.4	0.834	pathogenic
3	c.196A>G	p.Arg66Gly	switch II	I	4, 5	de novo	0.5326	26.9	0.836	pathogenic
3	c.203G>A	p.Arg68Gln	switch II	I	6, 7	de novo	0.6586	26.3	0.827	pathogenic
3	c.242G>T	p.Cys81Phe	β4	II	8	de novo	0.6280	30.0	0.840	pathogenic
3	c.247T>C	p.Ser83Pro	β4	II	9, 10	de novo	0.8283	27.8	0.853	pathogenic
4	c.476C>T	p.Ala159Val	NBP	II	11	de novo	1.0179	34.0	0.916	pathogenic
5	c.511G>Ab	p.Glu171Lys	CBR	III	12, 13–15	1 de novo, 1 familial	0.0158	24.7	0.768	pathogenic

Nucleotide numbering reflects cDNA numbering with 1 corresponding to the A of the ATG translation initiation codon in the CDC42 reference sequence (GenBank: NM_001791.3). No variants were reported in the public databases ExAC and GnomAD. All variants were predicted to be “deleterious” by Combined Annotation Dependent Depletion (CADD) v.1.3, Database for Nonsynonymous SNPs’ Functional Predictions (dbNSFP) Support Vector Machine (SVM) v.3.0, and REVEL algorithms.^{16, 17, 18} All changes satisfied the necessary criteria to be classified as pathogenic according to the American College of Medical Genetics guidelines.¹⁹ Abbreviations: NBP, nucleotide binding pocket; CBR, CRIB motif binding region.

^aScores > 0 (MetaSVM), > 15 (CADDphred) or > 0.5 (REVEL) predict that the sequence change has a significant impact on protein structure and function.

^bThis change affects transcript variant 1 (GenBank: NM_001791.3) and isoform 1 (GenBank: NP_001782.1), while it does not affect transcript variant 2 (GenBank: NM_044472.2) and isoform 2 (GenBank: NP_426359.1). The two isoforms have the same amino acid length but are characterized by a different C terminus.