Screening of premature ovarian insufficiency associated genes in Hungarian patients with next generation sequencing

Table 1 Potential causal variants found in 12 POI patients via targeted panel sequencing

Gene	ACMG	dbSNP ID	Sequence change		Type	ClinVar	MAF	Pathogenicity						Patient ID	Reference
Gene	ACMG	dbSNP ID	cDNA	AA	Type	ClinVar	MAF	P/B	CADD	VEST	SIFT	PolyPhen	GERP++	Patient ID	Reference
AIRE	VUS-P (PM2, BS2, PP3)	rs150634562	c.901G > A	V301M	Missense	VUS	< 0.01	22/4	25	0.53	0.02	0.95	3.86	P42	[17]
ATM	VUS (PM2, BP4)	rs762998620	c.680 C > T	S227L	Missense	VUS	< 0.01	4/22	23	0.19	0.04	0.01	4.45	P24	*
ATM	VUS (BP6)	rs34640941	c.4424 A > G	Y1475C	Missense	VUS	< 0.01	9/14	22	0.29	0.09	0.01	5.56	P26	*
DAZL	VUS (PM2)	-	c.863G > A	S288N	Missense	-	-	11/15	23	0.47	0.03	-	6.06	P09	*
DAZL	VUS-LP (PM2)	rs1360420397	c.380G > A	R127H	Missense	-	< 0.01	15/12	25	0.52	0.04	0.70	5.11	P36	*
EIF2B2	VUS-LP (PM2, PP2)	rs150617429	c.380 C > G	A127G	Missense	VUS	< 0.01	12/14	22	0.27	0.06	0.01	5.36	P22	[18]
GDF9	VUS (PM2, BP4)	rs1321340406	c.958G > A	G320S	Missense	-	< 0.01	3/24	17	0.08	0.31	0.02	3.85	P20	*
LHCGR	VUS-LP (PM2, PP3)	rs746197082	c.211G > C	G71R	Missense	-	< 0.01	22/6	25	0.78	0.05	1	5.89	P05	[19, 20]
POLG	VUS-P (PP2, PP3, PP5, BS2)	rs61752784	c.803G > C	G268A	Missense	VUS	< 0.01	10/2	25	0.99	0	1	5.48	P18, P20	[21]
USP9X	VUS-LP (PM2)	-	c.6722T > C	V2241A	Missense	-	-	16/9	24	0.72	0	-	5.56	P03	*
XPNPEP2	VUS-LP (PM2)	-	c.828delT	F276Lfs*12	Frameshift	-	-	1/0	-	0.29	-	-	5.78	P04	*
XPNPEP2	VUS-LP (BP1, BP4, PM2)	rs1308764609	c.460G > A	V154M	Missense	-	< 0.01	21/4	22	0.52	0	0.99	4.5	P19	*

VEST analysis generates values between 0 and 1, and scores ≥ 0.5 were classified as pathogenic variants and those < 0.5 as benign. CADD analysis generates a PHRED-like scaled value. Scores ≥ 20 were classified as pathogenic variants and those < 20 as benign. PolyPhen analysis generates values between 0 and 1, and scores 0.0 to 0.15 were predicted to be benign, 0.15 to 0.85 as possibly damaging and 0.85 to 1.0 as damaging. The SIFT score ranges from 0 to 1, and scores 0.0 to 0.05 were considered deleterious and 0.05 to 1.0 as tolerated. GERP + + scores range from − 12.3 to 6.17, with higher scores indicating higher evolutionary constraint. A score greater than 2 considered as constrained. Abbreviations: ACMG: American College of Medical Genetics, cDNA: complementary DNA, AA: amino acid change, MAF: minor allele frequency (gnomAD v3.1.2 non-Finnish (controls/biobanks), P/B: pathogenic/benign prediction.

ISSN: 1755-8794