Potential splice site variants identified in the VWD3 3WINTERS-IPS cohort
| EU/IR . | VWF Gene Defect . | Domain (IVS) . | varSEAK . | ASSP score (WT; MUT) threshold 4.5 (donor)/2.2 (acceptor) . | BDGP score (WT; MUT) threshold 0.40 . | NatGen2 (WT; MUT) . | ClinGen . | dbSNP(rs)– HGMD (CS) . | First reported . | mRNA study . |
|---|---|---|---|---|---|---|---|---|---|---|
| IR | NM_000552.3: c.220G>A (p.Gly74Arg) | D1(3) | Splicing effect | 13.65; <4.5 | 0.96; 0.52 | 0.99; 0.70 | VUS | – | ||
| IR | NM_000552.3: c.533-3C>G | D1 (5) | Splicing effect | 9.38; 4.95 | 0.90; <0.40 | 0.71; 0.43 | VUS | – | ||
| EU | NM_000552.3: c.533-2A>G | D1 (5) | – | – | – | – | LP | rs267607301 | 77 | 33 p.Thr179Profs*30 |
| EU | NM_000552.3: c.874 + 2T>C | D1 (7) | Splicing effect | 9.85; <4.5 | 0.80; <0.40 | 0.99; not detected | VUS | CS1310896 | 78 * | |
| IR | NM_000552.3: c.874+ 1G>A | D1 (7) | Splicing effect | 9.85; <4.5 | 0.80; <0.40 | 0.99; not detected | VUS | rs267607302 | 79 | |
| EU | NM_000552.3: c.1534-3C>A | D2 (13) | – | – | – | – | LP | rs61754009 | 72 | 34 p.Leu512Profs*11 |
| EU | NM_000552.3: c.1729 + 3A>C | D2 (14) | Likely splicing effect | 6.60; <4.5 | 0.17; <0.01 | 0.70; not detected | VUS | CS095425 | 32 * | |
| EU | NM_000552.3: c.1931_1945 + 5del | D2(15) | Splicing effect | 11.34; <4.5 | 0.48; <0.40 | 0.65; not detected | LP | CD942301 | 76 | |
| IR | NM_000552.3: c.1945 + 1G>T | D2 (15) | Splicing effect | 11.34; <4.5 | 0.48; <0.40 | 0.36; not detected | VUS | – | ||
| IR | NM_000552.3: c.2186 + 2T>C | D2 (16) | Splicing effect | 13.30; <4.5 | 1.00; <0.40 | 1.00; 0.70 | VUS | – | ||
| IR | NM_000552.3: c.2282-2A>G | D' (17) | Splicing effect | 3.58; <2.2 | 0.32; < 0.01 | 0.24; not detected | VUS | CS143311 | 55 | |
| EU | NM_000552.3: c.2443-1G>C | D' (18) | – | – | – | – | LP† | rs61748480 | 43 | 35 p.Val815Cysfs*15 |
| IR | NM_000552.3: c.2547-1G>C | D' (19) | Splicing effect | n.a. | 0.05; <0.01 | 0.55; not detected | VUS | . | ||
| IR | NM_000552.3: c.3222 + 2dupT | D3 (24) | Splicing effect | n.a. | 0.97; <0.40 | 0.95; not detected | VUS | |||
| IR | NM_000552.3: c.3379 + 2T>C | D3 (25) | Splicing effect | 10.05; <4.5 | 0.90; <0.40 | 0.95; not detected | VUS | . | ||
| EU | NM_000552.3: c.3379 + 1G>A | D3 (25) | Splicing effect | 10.05;<4.5 | 0.90; <0.40 | 0.95; not detected | P† | rs2363337 | 81 | |
| IR | NM_000552.3: c.3675-1G>A | D3 (27) | Splicing effect | 9.27; <2.2 | 0.97; <0.40 | 0.95; not detected | LP† | rs746457842 | 46 | |
| EU | NM_000552.3: c.5170 + 1G>A | A3 (29) | Splicing effect | 12.33; <4.5 | 0.84; <0.40 | 0.83; not detected | LP | rs764543553 | ||
| EU | NM_000552.3: c.5170 + 10C>T | A3 (29) | – | – | – | – | LB† VUS† | rs61750601 | 31,42 | 33 (No splicing alteration) |
| EU | NM_000552.3: c.5455 + 2T>C | A3 (31) | Splicing effect | 12.02; <4.5 | 0.89; <0.40 | 0.71; 0.06 | VUS | CS1310562 | 59 | |
| IR | NM_000552.3: c.6901 + 1G>T | C1 (39) | Splicing effect | 13.93; <4.5 | 0.98; <0.40 | 0.99; not detected | VUS | – | ||
| EU | NM_000552.3: c.7082-2A>G | C2 (41) | – | – | – | – | LP | rs267607358 | 63 * | 33 (Nonsense mediated decay) |
| EU | NM_000552.3: c.7082-13G>C | C2 (41) | No splicing effect | 7.48; 8.79 | 0.72; 0.77 | 0.00; 0.00 | VUS† | rs71581025 | ||
| EU | NM_000552.3: c.7287 + 1G>C | C2 (42) | Splicing effect | 11.26; <4.5 | 1.00; <0.40 | 0.93; not detected | VUS | – | ||
| EU | NM_000552.3: c.7729 + 7C>T | C4 (45) | – | – | – | – | P | rs61751301 | 42 * | 36 p.Glu2577Glyfs*21 |
| EU | NM_000552.3: c.7730-1G>C | C4 (45) | – | – | – | – | LP | rs267607366 | 63 | 33 p.Glu2577Alafs*58 |
| EU | NM_000552.3: c.7770 + 1G>T | C4 (46) | – | – | – | – | LP | – | 37 * | 37 (Three alternative splicing) |
| EU | NM_000552.3: c.7887 + 2T>A | C4 (47) | Splicing effect | 13.80; <4.5 | 0.99; <0.40 | 0.93; not detected | VUS | rs113814258 | ||
| EU | NM_000552.3: c.8155 + 6T>C | C6 (50) | – | – | – | – | LP | rs1223422347 - CS100200 | 38 * | 38 p.Gly2706Valfs*25 |
| EU | NM_000552.3: c.8155 + 3G>C | C6 (50) | – | – | – | – | LP | rs61751304 | 63 * | 33 p.Gly2706Valfs*25 |
| EU | NM_000552.3: c.8155 + 3G>A | C6 (50) | No splicing effect | 11.67; 12.35 | 0.94; 0.99 | 0.60; 0.63 | VUS | CS1211912 | 81 * | |
| EU | NM_000552.3: c.8155 + 1G>T | C6 (50) | – | – | – | – | LP | rs746457842 | 36 | 36 p.G2706_C2719delfs*25 |
| EU/IR . | VWF Gene Defect . | Domain (IVS) . | varSEAK . | ASSP score (WT; MUT) threshold 4.5 (donor)/2.2 (acceptor) . | BDGP score (WT; MUT) threshold 0.40 . | NatGen2 (WT; MUT) . | ClinGen . | dbSNP(rs)– HGMD (CS) . | First reported . | mRNA study . |
|---|---|---|---|---|---|---|---|---|---|---|
| IR | NM_000552.3: c.220G>A (p.Gly74Arg) | D1(3) | Splicing effect | 13.65; <4.5 | 0.96; 0.52 | 0.99; 0.70 | VUS | – | ||
| IR | NM_000552.3: c.533-3C>G | D1 (5) | Splicing effect | 9.38; 4.95 | 0.90; <0.40 | 0.71; 0.43 | VUS | – | ||
| EU | NM_000552.3: c.533-2A>G | D1 (5) | – | – | – | – | LP | rs267607301 | 77 | 33 p.Thr179Profs*30 |
| EU | NM_000552.3: c.874 + 2T>C | D1 (7) | Splicing effect | 9.85; <4.5 | 0.80; <0.40 | 0.99; not detected | VUS | CS1310896 | 78 * | |
| IR | NM_000552.3: c.874+ 1G>A | D1 (7) | Splicing effect | 9.85; <4.5 | 0.80; <0.40 | 0.99; not detected | VUS | rs267607302 | 79 | |
| EU | NM_000552.3: c.1534-3C>A | D2 (13) | – | – | – | – | LP | rs61754009 | 72 | 34 p.Leu512Profs*11 |
| EU | NM_000552.3: c.1729 + 3A>C | D2 (14) | Likely splicing effect | 6.60; <4.5 | 0.17; <0.01 | 0.70; not detected | VUS | CS095425 | 32 * | |
| EU | NM_000552.3: c.1931_1945 + 5del | D2(15) | Splicing effect | 11.34; <4.5 | 0.48; <0.40 | 0.65; not detected | LP | CD942301 | 76 | |
| IR | NM_000552.3: c.1945 + 1G>T | D2 (15) | Splicing effect | 11.34; <4.5 | 0.48; <0.40 | 0.36; not detected | VUS | – | ||
| IR | NM_000552.3: c.2186 + 2T>C | D2 (16) | Splicing effect | 13.30; <4.5 | 1.00; <0.40 | 1.00; 0.70 | VUS | – | ||
| IR | NM_000552.3: c.2282-2A>G | D' (17) | Splicing effect | 3.58; <2.2 | 0.32; < 0.01 | 0.24; not detected | VUS | CS143311 | 55 | |
| EU | NM_000552.3: c.2443-1G>C | D' (18) | – | – | – | – | LP† | rs61748480 | 43 | 35 p.Val815Cysfs*15 |
| IR | NM_000552.3: c.2547-1G>C | D' (19) | Splicing effect | n.a. | 0.05; <0.01 | 0.55; not detected | VUS | . | ||
| IR | NM_000552.3: c.3222 + 2dupT | D3 (24) | Splicing effect | n.a. | 0.97; <0.40 | 0.95; not detected | VUS | |||
| IR | NM_000552.3: c.3379 + 2T>C | D3 (25) | Splicing effect | 10.05; <4.5 | 0.90; <0.40 | 0.95; not detected | VUS | . | ||
| EU | NM_000552.3: c.3379 + 1G>A | D3 (25) | Splicing effect | 10.05;<4.5 | 0.90; <0.40 | 0.95; not detected | P† | rs2363337 | 81 | |
| IR | NM_000552.3: c.3675-1G>A | D3 (27) | Splicing effect | 9.27; <2.2 | 0.97; <0.40 | 0.95; not detected | LP† | rs746457842 | 46 | |
| EU | NM_000552.3: c.5170 + 1G>A | A3 (29) | Splicing effect | 12.33; <4.5 | 0.84; <0.40 | 0.83; not detected | LP | rs764543553 | ||
| EU | NM_000552.3: c.5170 + 10C>T | A3 (29) | – | – | – | – | LB† VUS† | rs61750601 | 31,42 | 33 (No splicing alteration) |
| EU | NM_000552.3: c.5455 + 2T>C | A3 (31) | Splicing effect | 12.02; <4.5 | 0.89; <0.40 | 0.71; 0.06 | VUS | CS1310562 | 59 | |
| IR | NM_000552.3: c.6901 + 1G>T | C1 (39) | Splicing effect | 13.93; <4.5 | 0.98; <0.40 | 0.99; not detected | VUS | – | ||
| EU | NM_000552.3: c.7082-2A>G | C2 (41) | – | – | – | – | LP | rs267607358 | 63 * | 33 (Nonsense mediated decay) |
| EU | NM_000552.3: c.7082-13G>C | C2 (41) | No splicing effect | 7.48; 8.79 | 0.72; 0.77 | 0.00; 0.00 | VUS† | rs71581025 | ||
| EU | NM_000552.3: c.7287 + 1G>C | C2 (42) | Splicing effect | 11.26; <4.5 | 1.00; <0.40 | 0.93; not detected | VUS | – | ||
| EU | NM_000552.3: c.7729 + 7C>T | C4 (45) | – | – | – | – | P | rs61751301 | 42 * | 36 p.Glu2577Glyfs*21 |
| EU | NM_000552.3: c.7730-1G>C | C4 (45) | – | – | – | – | LP | rs267607366 | 63 | 33 p.Glu2577Alafs*58 |
| EU | NM_000552.3: c.7770 + 1G>T | C4 (46) | – | – | – | – | LP | – | 37 * | 37 (Three alternative splicing) |
| EU | NM_000552.3: c.7887 + 2T>A | C4 (47) | Splicing effect | 13.80; <4.5 | 0.99; <0.40 | 0.93; not detected | VUS | rs113814258 | ||
| EU | NM_000552.3: c.8155 + 6T>C | C6 (50) | – | – | – | – | LP | rs1223422347 - CS100200 | 38 * | 38 p.Gly2706Valfs*25 |
| EU | NM_000552.3: c.8155 + 3G>C | C6 (50) | – | – | – | – | LP | rs61751304 | 63 * | 33 p.Gly2706Valfs*25 |
| EU | NM_000552.3: c.8155 + 3G>A | C6 (50) | No splicing effect | 11.67; 12.35 | 0.94; 0.99 | 0.60; 0.63 | VUS | CS1211912 | 81 * | |
| EU | NM_000552.3: c.8155 + 1G>T | C6 (50) | – | – | – | – | LP | rs746457842 | 36 | 36 p.G2706_C2719delfs*25 |
Variants reported in bold are not listed in the EAHAD,17 HGMD,18 or Ensembl19 databases. Splice prediction tools: varSEAK, Alternative Splice Site Predictor (ASSP),25 Berkeley drosophila genome project (BDGP),26 NatGen2.27 ClinGen: P = Pathogenic; LP = Likely pathogenic; LB = likely benign; VUS = uncertain significance.
IVS, intervening sequence; n.a., native splice site not identified by the prediction tool.
Indicates that the previous publication was concerning the same patient evaluated in this study.
Prediction already reported in ClinVar.