Molecular features and predicted pathogenicity of 23 mutations in collagen IV genes, found in 11 patients with Alport syndrome
| Collagen domain affected (for missense mutation) | Pathogenicity* | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DNA variant | Type | Exon (intron) number | dbSNP reference ID | Predicted effect on the protein | SIFT (score)† | Mutation taster (p value)‡ | PolyPhen2 (score)§ | SpliceSite Finder | MaxEntScan | NNSPLICE | GeneSplicer | Human Splicing Finder | References | |
| COL4A3 | ||||||||||||||
| del ex 1 | Deletion | 1 | – | Whole gene deletion | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| c.898G>A | Missense | 16 | – | p.Gly300Arg | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | LOVD |
| c.1504+1G>A | Misplicing Lost 5′ splice site Canonical GT | (23) | – | p.? | NA | NA | NA | NA | SL | SL | SL | SL | SL | 26 |
| c.1558G>C | Missense | 24 | Pending | p.Gly520Arg | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | 26 |
| c.2065G>A | Missense | 28 | Pending | p.Gly689Arg | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | 26 |
| c.2746+1G>T | Misplicing Lost 5′ splice site Canonical GT | (33) | – | p.? | NA | NA | NA | NA | SL | SL | SL | SL | RA | |
| c.4994G>A | Missense | 52 | rs376550779 | p.Cys1665Tyr | NC1 | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | LOVD |
| COL4A4 | ||||||||||||||
| c.[1−?_192+?del] | Deletion | 1–4 | – | Whole gene deletion | NA | NA | NA | NA | NA | NA | NA | NA | NA | 26 |
| c.1293_1310del | In-frame deletion | 20 | – | p.Lys434_Gly439del | Collagenous | NA | NA | NA | NA | NA | NA | NA | NA | |
| c.1459+1G>A | Misplicing Lost 5′ splice site Non canonical GC | (21) | – | p.? | NA | NA | NA | NA | SL | ND | CS | ND | ND | |
| c.1553G>A | Missense | 22 | – | p.Gly518Glu | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | |
| c.1623+5G>T | Misplicing Lost 5′ splice site Consensus branch site | (22) | – | p.? | NA | NA | NA | NA | SL | SL | SL | SL | RA | |
| c.2075G>T | Missense | 27 | Pending | p.Gly692Val | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | 26 |
| c.2164G>A | Missense | 27 | – | p.Gly722Ser | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | |
| c.2906C>G22 | Nonsense | 32 | rs35138315 | p.Ser969X | Collagenous | NA | NA | NA | NA | NA | NA | NA | NA | LOVD26 |
| c.3452G>C | Missense | 37 | rs371803356 | p.Gly1151Ala | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | |
| c.3817+1G>T | Misplicing Lost 5′ splice site | (40) | – | p.? | NA | NA | NA | NA | SL | SL | SL | SL | SL | |
| c.4698delT | Frame shift | 47 | – | p.Cys1566Trpfs*37 | NC1 | NA | NA | NA | NA | NA | NA | NA | NA | 26 |
| c.4760C>G | Missense | 47 | rs190148408¶ | p.Pro1587Arg | NC1 | D (0.01) | P (1) | PD (0.913) | NA | NA | NA | NA | NA | |
| COL4A5 | ||||||||||||||
| c.1931G>A | Missense | 25 | Pending | p.Gly644Asp | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | LOVD26 |
| c.2051G>T | Missense | 27 | rs104886160** | p.Gly684Val | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | 42 |
| c.2858G>T | Missense | 33 | rs78972735**,†† | p.Gly953Val | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | 43 44 |
| c.4042G>A | Missense | 46 | – | p.Gly1348Arg | Collagenous | D (0) | DC (1) | PD (1) | NA | NA | NA | NA | NA | |
*Pathogenicity predicted using Alamut software V.2.3 (Interactive Biosoftware, Rouen, France), indicating functional impact of variants with relevant prediction tools. For missense variants, data derived from SIFT, MutationTaster and PolyPhen-2 are detailed. Splicing predictions included MaxEntScan, NNSPLICE, Human Splicing Finder, SpliceSiteFinder, GeneSplicer predictions tools.
†Substitutions with normalised probabilities <0.05 are predicted to be deleterious, those ≥0.05 are predicted to be tolerated.
‡p Value indicates the security of the prediction as either ‘disease-causing’ or ‘polymorphism’, with 1 being most secure.
§Benign, possibly damaging and probably damaging correspond to posterior probability intervals [0, 0.2], (0.2, 0.85) and [0.85, 1], respectively.
¶Minor allele (C) frequency/count=0.003/6.
**dbSNP clinical significance, pathogenic.
††Minor allele (T) frequency/count=0.003/5.
AC, activating a cryptic 5′ splice site; D, deleterious; DC, disease-causing; LOVD, Leiden Open Variation Database (available at http://lovd.nl/3.0/home); NA, not applicable; ND not determined by the tool; P, polymorphism; PD, probably damaging; RA, reduced affinity of the affected sequences for the appropriate splicing factors; SL, loss of splice site.