Nonsense or Frameshift
Predicted to undergo NMD b
Not predicted to undergo NMD b
Exon is present in biologically-relevant transcript(s) and truncation between codons 1-581
Exon is absent from biologically-relevant transcript(s)
PVS1
N/A
Truncated/altered region is critical to protein function (codons 582-620)
Role of region in protein function is unknown (codons 621-676)
LoF variants in this exon are frequent in the general population and/or exon is absent from biologically-relevant transcript(s)
PVS1_Moderate
N/A
PVS1_Supp
PVS1_Supp
LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcript(s)
Variant removes >10% of protein
Variant removes <10% of protein
GT--AG
1,2 splice
sites a
Exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD b
Exon skipping or use of a cryptic splice site preserves reading frame
Truncated/altered region is critical to protein function (codons 582-620) c
Role of region in protein function is unknown (codons 621-676)
LoF variants in this exon are frequent in the general population and/or exon is absent from biologically-relevant transcript(s)
LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcript(s)
Variant removes >10% of protein
Truncated/altered region is critical to protein function c
PVS1_Moderate
N/A
PVS1_Supp
PVS1_Supp
PVS1_Strong
Variant removes <10% of protein
Exon skipping or use of a cryptic splice site disrupts reading frame and is NOT predicted to undergo NMD b
Deletion
(Single exon to full gene)
Single to multi exon deletion –
Disrupts reading frame and is predicted to undergo NMD b
Single to multi exon deletion –
Preserves reading frame
Full gene deletion
Exon is present in biologically-relevant transcript(s)
Truncated/altered region is critical to protein function c
Exon is absent from biologically-relevant transcript(s)
Role of region in protein function is unknown
LoF variants in this exon are frequent in the general population and/or exon is absent from biologically-relevant transcript(s)
PVS1 d
Truncated/altered region is critical to protein function c
PVS1
N/A
PVS1_Strong
N/A
PVS1_Strong
PVS1_Moderate
PVS1_Strong
Duplication
(≥1 exon in size and must be completely contained within gene)
Proven in tandem
Presumed in tandem
Proven not in tandem
Reading frame disrupted and NMD predicted to occur
No or unknown impact on reading frame and NMD
Reading frame presumed disrupted and NMD predicted to occur
PVS1
N/A
PVS1_Strong
N/A
Initiation Codon
Different functional transcript uses alternative start codon
No known alternative start codon in other transcripts
≥1 pathogenic variant(s) upstream of closest potential in-frame start codon
No pathogenic variant(s) upstream of closest potential in-frame start codon
PVS1_Supp
PVS1_Moderate
N/A
Single to multi exon deletion –
Disrupts reading frame and is NOT predicted to undergo NMD b
LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcript(s)
Variant removes >10% of protein
Variant removes <10% of protein
Role of region in protein function is unknown
LoF variants in this exon are frequent in the general population and/or exon is absent from biologically-relevant transcript(s)
LoF variants in this exon are not frequent in the general population and exon is present in biologically-relevant transcript(s)
Variant removes >10% of protein
N/A
PVS1_Strong
PVS1_Moderate
Variant removes <10% of protein
Evidence that truncation between codons 530-581 is not subject to NMD
PVS1_Strong
Exon is present in biologically-relevant transcript(s) and truncation between codons 1-581
Exon is absent from biologically-relevant transcript(s)
PVS1
N/A
Evidence that truncation between codons 530-581 is not subject to NMD
PVS1_Strong