The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism

Table 4

Further genetic pathogenicity analysis of 12 children with IHH (excluding benign or likely benign variants).

Case	Gene	Variant	Amino acid	Source of variant	Mutation taster	CADD_raw	CADD_phred	MetaSVM_score	Classification (ACMG)
KS1	CHD7	c.2442+1G>A	/	De novo	1	/	/	/	P (PVS1, PS2, PM2, PP3, PP4)
KS2	CHD7	c.2744A>G	p.D915G	Paternal	0.999	4.436	32	0.31	LP (PM1, PM2, PP3, PP4)
KS4	CHD7	c.2698-1G>T	/	Paternal	1	/	/	/	P (PVS1, PM2, PP3)
KS5	CHD7	c.2724G>T	p.W908C	Maternal	1	4.566	32	1.068	LP (PM1, PM2, PP3, PP4)
KS6	NDNF	c.1439T>A	p.I480N	Paternal	0.999	4.094	28.5	0.508	US (PM2, PP2, PP3)
nHH1	CHD7	c.749G>A	p.R250H	Paternal	0.999	3.505	25	0.08	US (PP3, PP4)
nHH3	CHD7	c.59G>A	p.G20D	Maternal	0.986	2.865	23.3	1.045	US (PP3, PP4)
nHH4	CHD7	c.2182G>A	p.D728N	Paternal	0.999	2.819	23.2	0.488	US (PP3, PP4)
nHH5	FGFR1	c.1271G>A	p.R424H	Paternal	0.999	3.489	24.9	0.062	US (PM2, PP3, PP4)
	SEMA3A	c.1369A>G	p.T457A	Maternal	0.999	3.672	25.6	1.111	US (PM2, PP2, PP3, PP5, PP6)
nHH6	FGF8	c.368G>A	p.G123E	Maternal	0.999	3.812	26.3	1.017	US (PM2, PP3, PP6)
nHH7	PROKR2	c.891_892insA	p.R298Tfs2	Paternal	/	/	/	/	P (PVS1, PM2, PM4, PP4)
nHH8	CHD7	c.4153G>C	p.D1385H	De novo	0.999	4.305	31	1.004	P (PS2, PM1, PM2, PP3, PP4)

: Splice Site Score Calculation and SpliceAI for Splicing Sites: Test positive. The 12 variants predicted by MutationTaster are all classified as "pathogenic". CADD_raw is the initial score, and CADD_phred is the converted score. The higher the score, the greater the harmful effect.The CADD_phred score is recommended to be greater than 15. MetaSVM fractional cut value is 0.0 (higher score indicates greater harmful effects). ACMG: American College of Medical Genetics Laboratory Practice Committee Working Group, Described as P:pathogenic; LP:likely pathogenic; US: uncertain significance. B: benign ;LB: likely benign. PVS: pathogenic very strong, PS: pathogenic strong, PM: pathogenic moderate,PP: pathogenic supporting.