Genetic analysis of osteopetrosis in Pakistani families identifies novel and known sequence variants

BMC Medical Genomics

Table 2 List of potential disease causal variants identified in this study

Family ID	Genomic change (GRCh37/hg19)	Canonical transcript change	Function	MAF gnomAD^† SAS	MAF gnomAD Global	Evidence of pathogenicity^§	Variant classification^§	Reference
OP1	Chr11:67810849G > A	TCIRG1:NM_006019.4:c.515G > A:p.Gly172Asp	Nonsynonymous SNV	–	–	PM2 PP3 PP4	Uncertain significance	This study
OP2	Chr11:67811644-67811645delGT	TCIRG1:NM_006019.4:c.854_855del:p.Val285Alafs*204	Frameshift deletion	–	–	PVS1 PM2 PM4 PP1 PP3 PP4	Pathogenic	This study
OP3	Chr16:1496634A > T	CLCN7:NM_001287.6:c.2416 T > A:p.806Argext58	Stoploss	–	–	PM2 PM4 PP3 PP4	Likely pathogenic	This study
OP4	Chr11:67811761insG	TCIRG1:NM_006019.4:c.971dup:p.Cys324Trpfs*166	Frameshift insertion	–	–	PVS1 PM2 PS1 PP1 PP3 PP4	Pathogenic	Sobacchi et al. [11]
OP5	Chr11:67812570G > A	TCIRG1:NM_006019.4:c.1165 + 1G > A	Splicing	–	–^¶	PVS1 PM2 PP3 PP4	Pathogenic	This study^¶¶
OP6	Chr11:67815441T > A	TCIRG1:NM_006019.4:c.1554 + 2T > A	Splicing	0.0002	0.00002	PVS1 PM2 PP1 PP3 PP4	Pathogenic	Sobacchi et al. 11
OP7	Chr11:67816344A > G	TCIRG1:NM_006019.4:c.1555-2A > G	Splicing	–	–^¶¶¶	PVS1 PM2 PP3 PP4 PP5	Pathogenic	This study^¶¶¶¶
OP8	Chr6:108395732delC	OSTM1:NM_014028.4:c.124del:p.Val42Serfs*57	Frameshift deletion	–	–	PVS1 PM2 PP3 PP4	Pathogenic	This study
OP9	Chr16:1496634A > T	CLCN7:NM_001287.6:c.2416T > A:p.806Argext58	Stoploss	–	–	PM2 PM4 PP3 PP4	Likely pathogenic	This study
OP10	Chr11:67811761insG	TCIRG1:NM_006019.4:c.971dup:p.Cys324Trpfs*166	Frameshift insertion	–	–	PVS1 PM2 PS1 PP1 PP3 PP4	Pathogenic	Sobacchi et al. 11

MAF minor allele frequency, SAS South Asian population, – absent
^†v2.1.1 accessed May 7th, 2021
^§Determined using wInterVar online tool (PMID: 28132688) and following the ACMG guidelines for variant interpretation (PMID: 25741868)
^¶MAF of a different nucleotide change (G > C) at the same position is 0.000004
^¶¶A different nucleotide change (G > C) at the same position reported as heterozygous disease variant by Allgrove, J., and Shaw, N.J. (2015)
^¶¶¶MAF of a different nucleotide change (A > C) at the same position is 0.00001
^¶¶¶¶Two ClinVar entries (RCV001040779, RCV000666560) exist for different nucleotide change (A > C) at the same position
PM2, Variant absent from controls or present at extremely low frequency if recessive
PP3, Multiple lines of computational evidence support a deleterious effect
PP4, Patient's phenotype or family history is highly specific for a disease with a single genetic etiology
PVS1, Null variant in a gene where loss of function is a known mechanism of disease
PM4, Variant causing protein length changes
PP1, Cosegregation with disease in affected family members in a gene definitively known to cause the disease
PS1, Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
PP5, Reported as pathogenic in reputable source, but not independent evaluated

ISSN: 1755-8794