Table 1.

Sequence variations in BOC

Singleton patient	Four gene screena	BOC gDNA [hg19]	BOC cDNA [NM_033254.2]b	BOC Protein [NP_150279.1]	Protein domain	Consensus Predictiond	Experiment	ExAC MAF	ACMGe	ACMG predictione
BL9321f	ZIC2 c.1206C>G; p.Y402*	chr3:112969488 C/T chr3:112997000 G/T (phase not known)	c.184C>T c.1598G>T	p.Pro62Ser p.Arg533Leu	Ig FN1	Benign Benign	N.T. Suppressor of gain of function	0.000008238 0.000008237	BP4/BP5 BP4/BP5	Likely benign Likely benign
LCL100 g	Normal	chr3:112997069 G/A	c.1667G>A	p.Gly556Glu	FN1	Damaging	Gain of function	None	PM2;PP3	VOUS
FB604	Normal	chr3:112998740 G/C	c.2090G>C	p.Arg697Pro	linker FN2 to FN3	Damaging	Benign	0.0005543	PP3;BS1	VOUS
BL1062	Normal	chr3:112998761 A/C	c.2111A>C	p.Tyr704Ser	linker FN2 to FN3	Benign	N.T.	0.0003142	BS1;BP4	Likely benign
BL6788	Normal	chr3:113002309 C/G	c.2483C>G	p.Pro828Argc	linker FN3 to TM	Benign	Suppressor of gain of function	0.001668	BS1;BP4	Likely benign
BL7348 h	del TGIF/dup 18p	chr3:113002309 C/G	c.2483C>G	p.Pro828Argc	linker FN3 to TM	Benign	Suppressor of gain of function	0.001668	BS1;BP4/BP5	Benign
BL6768 i	Normal	chr3:113002401 G/A	c.2575G>A	p.Gly859Arg	TM	Damaging	N.T.	0.00002471	PP3	VOUS
BL9282 j	Normal	chr3:113005589 T/A	c.3225T>A	p.Ser1075Arg	intracellular	Benign	N.T.	0.0001979	BS1;BP4	Likely benign

^aPineda-Alvarez et al. (2010) by Sanger sequencing or cytogenetic analysis.

^bVariant screening of BOC (MIM#608708) was essentially identical to that described in Kauvar et al. 2010 with Sanger sequencing as confirmation. Minor Allele Frequency (MAF) as determined by ExAC [http://exac.broadinstitute.org].

^cAlso detected in a healthy parent of an HPE child, a product of a first cousin marriage.

^ddbNSFP v.3.3a consensus (http://annovar.openbioinformatics.org/en/latest/): determined by concurrence >50% of [SIFT, PolyPhen2HDIV, PolyPhenHVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, FATHMM-MKL, MetaSVM, MetaLR] as damaging or <50% as benign.

^eJustifications for assertions of pathogenicity incorporate the principal accepted guidelines in Richards, S. et al. (2015) for a simple autosomal dominant disorder with high penetrance. Variants with an allele frequency greater than 1;10,000 (the live birth incidence of HPE in the newborn nursery) are either likely benign or, if shown to be abnormal in function, can act as modifiers.

^fSemilobar HPE, microcephaly, elevated palate, hypotelorism, global developmental delay, spasticity, diabetes insipidus.

^gSemilobar HPE, hypoplastic corpus callosum, asymmetric hydrocephalous, generalized atrophy, brachycephaly.

^hHypotelorism, microcephaly, cebocephaly, cleft lip.

^ILobar HPE, midline cleft lip and palate.

^jLobar HPE.