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

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

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.*806Argext*58 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.*806Argext*58 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
  1. MAF minor allele frequency, SAS South Asian population, – absent
  2. v2.1.1 accessed May 7th, 2021
  3. §Determined using wInterVar online tool (PMID: 28132688) and following the ACMG guidelines for variant interpretation (PMID: 25741868)
  4. MAF of a different nucleotide change (G > C) at the same position is 0.000004
  5. ¶¶A different nucleotide change (G > C) at the same position reported as heterozygous disease variant by Allgrove, J., and Shaw, N.J. (2015)
  6. ¶¶¶MAF of a different nucleotide change (A > C) at the same position is 0.00001
  7. ¶¶¶¶Two ClinVar entries (RCV001040779, RCV000666560) exist for different nucleotide change (A > C) at the same position
  8. PM2, Variant absent from controls or present at extremely low frequency if recessive
  9. PP3, Multiple lines of computational evidence support a deleterious effect
  10. PP4, Patient's phenotype or family history is highly specific for a disease with a single genetic etiology
  11. PVS1, Null variant in a gene where loss of function is a known mechanism of disease
  12. PM4, Variant causing protein length changes
  13. PP1, Cosegregation with disease in affected family members in a gene definitively known to cause the disease
  14. PS1, Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
  15. PP5, Reported as pathogenic in reputable source, but not independent evaluated