Table 1.
characteristics of the patients with SMAD6 variants.
| Patient | Sex | Age of molecular diagnosis (months) | Affected suture | Exon | Genomic position (hg38) chr15 | MAF max (gnomADv3) NM_005585.4: | Protein | dbSNP | MAF max/MAF total gnomADv3 | SIFT | Polyphen HumVar | CADD | Fathmm | REVEL | Meta LR | Maxent | SpliceAI (score 0–1) | SPIP risk [0–100%] | HGMD-pro | Clinvar | Inheritance | HGMD parameters | HGMD classification |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 10 | metopic | 1 | g.66703301 C > T | c.43 C > T | p,(Arg15*) | rs766270982 | 0.000013/0.000013 | - | - | 40 | - | - | 0 | 2.5% | yes | No | unaffected mother | PVS1, PM2, PP4 | P | ||
| 2 | M | 8 | metopic | 1 | g.66703723_66703729del | c.465_471del | p.(Gly156Valfs*23) | rs958818801 | 0.000013/0.00002 | - | - | 29 | - | - | 0 | 2.5% | No | VSI radioulnar synostosis and aortic valve | unaffected father | PVS1, PM2, PP4 | P | ||
| 3 | F | 9 | metopic | 1 | g.66704051 C > T | c.793 C > T | p,(His265Tyr) | no | not described | D | PD | 26.4 | D | D | D | 0 | 02.51% | No | VSI radioulnar synostosis | unaffected mother | PM1, PM2, PP3, PP4 | LP | |
| 4 | M | 7 | metopic | 1 | g.66704075 G > A | c.817 G > A | p.(Glu273Lys) | rs1259557323 | 0.000013/0.000013 | D | PD | 35 | D | D | D | DL:−48% | DL:−48% | 98.4% | No | No | unaffected mother | PP3, PP4, PM2 | LP |
| 5 | F | 8 | sagittal | 2 | g.66711728 A > G | NM_005585.4: c.874 + 4 A > G | p.? | rs375338619 | 0.00004/ 0.00005 | - | - | 22.4 | - | - | - | DL:−30% DG:+350% | DL:0.89 | 85.9% | No | No | unaffected father | PP3, PP4, PM1, PM2 | LP |
| 1 | NM_001142861.2: c.91 + 4 A > G | ||||||||||||||||||||||
| 6 | M | 12 | metopic | 2 | g.66711707 A > G | c.857 A > G | p.(Asp286Gly) | rs138466588 | 0.00015/ 0.00004 | D | PD | 24.9 | D | D | D | 0 | 23.6% | No | No | unavailable father | PM1, PP3, PP4 | VUS | |
| 7 | M | 85 | metopic | 4 | g.66781340dup | c.1296dupC | p.(Gly433Argfs*132) | no | 0.00003/ 0.00003 | - | - | 33 | - | - | - | - | 0 | 2% | yes | yes | unavailable | PVS1, PM2, PP4 | P |
All frequencies from GnomAD and HGMD-pro. SPIP: the risk for the variant to alter splicing [79.27–91.06%].
D damaging, PD possibly damaging, B benign, AG acceptor gain, AL acceptor loss, DL donor loss, DG donor gain, SA South Asian, AF African/African American, LP likely pathogenic, P pathogenic.