Table 1.
Novel HGD gene variants identified in 172 patients with AKU
| DB-ID (variant code) in HGD mutation database | Exon/intron | Short name | DNA change | Predicted protein change | Type of variant | PolyPhen2 prediction (pph2_prob) | SNAP predictions (RI, expected accuracy) | mCSM proposed effect | protomer_DUET (ΔΔG kcal/mol) | mCSM_PPI (ΔΔG kcal/mol) | H.10 | Affected structure | Country of origin | rsID | Allele frequency (gnomAD) | Allele frequency (ExAC) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AKU_00200 | 1,2,3,4 | ex1,2,3,4 del | c.(?_1)_(282+1_283-1)del | p.(?) | Deletion | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Germany/Peru | n.i. | n.i. | n.i. |
| AKU_00176 | 2i | in2 del | c.87+8_88-31del | p.(?) | Deletion/effect on splicing | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Jordan | n.i. | n.i. | n.i. |
| AKU_00197 | 5,6 | ex5,6 del | c.(282+1_283-1)_(434+1_435-1)del | p.(?) | Deletion | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Mali | n.i. | n.i. | n.i. |
| AKU_00196 | 13 | ex13 del | c.(1006+1_1007-1)_(1188+1_1189-1)del | p.(?) | Deletion | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Italy | n.i. | n.i. | n.i. |
| AKU_00204 | 13i14 | in13ex14 del | c.1189-41_1248del | p.(?) | Deletion | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Iran | n.i. | n.i. | n.i. |
| AKU_00203 | 10 | A218_N219insKI | c.656_657insAATCAA | p.(Ala2018_Asn219insLysIle) | Insertion | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Italy | n.i. | n.i. | n.i. |
| AKU_00178 | 13 | G372_P373delinsA | c.1115_1117delGAC | p.(Gly372_Pro373delinsAla) | Deletion–insertion | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Poland | n.i. | n.i. | n.i. |
| AKU_00182 | 2 | Q29fs | c.85delC | p.(Gln29Argfs*82) | Frameshift | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Algeria | n.i. | n.i. | n.i. |
| AKU_00175 | 4 | R63fs | c.184_187dupTATA | p.(Arg63Ilefs*2) | Frameshift | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Poland | n.i. | n.i. | n.i. |
| AKU_00194 | 2 | D18Y | c.52G>T | p.(Asp18Tyr) | Missense | Probably damaging (1.000) | Effect (12, 59%) | Protomer destablization, Hexamer disruption | −0.611 | −0.859 | 0.36 | n.i. | Italy | n.i. | n.i. | n.i. |
| AKU_00177 | 5 | W97C | c.291G>C | p.(Trp97Cys) | Missense | Probably damaging (1.000) | Effect (59, 75%) | Protomer destablization | −1.222 | −0.765 | 0.01 | n.i. | Poland | n.i. | n.i. | n.i. |
| AKU_00181 | 7 | S150L | c.449C>T | p.(Ser150Leu) | Missense | Possibly damaging (0.856) | Effect (19, 59%) | Hexamer disruption | −0.195 | −1.625 | 0.34 | n.i. | Sweden | n.i. | n.i. | n.i. |
| AKU_00174 | 7 | G152R | c.454G>A | p.(Gly152Arg) | Missense | Probably damaging (1.000) | Effect (66, 80%) | Protomer destablization, Hexamer disruption | −0.926 | −2.141 | 0.01 | n.i. | Austria | n.i. | n.i. | n.i. |
| AKU_00195 | 8 | G170S | c.508G>A | p.(Gly170Ser) | Missense | Probably damaging (0.999) | Effect (65, 80%) | Protomer destablization, Hexamer disruption | −1.632 | −1.290 | 0.00 | n.i. | Italy | n.i. | n.i. | n.i. |
| AKU_00187 | 8 | G170A | c.509G>C | p.(Gly170Ala) | Missense | Probably damaging (0.997) | Effect (69, 80%) | Protomer destablization, Hexamer disruption | −0.484 | −1.004 | 0.00 | n.i. | Algeria/Spain | n.i. | n.i. | n.i. |
| AKU_00185 | 9 | G185R | c.553G>A | p.(Gly185Arg) | Missense | Probably damaging (0.999) | Effect (90, 95%) | Protomer destablization, Hexamer disruption | −0.876 | −2.200 | 0.03 | n.i. | France/Belgium | n.i. | n.i. | n.i. |
| AKU_00186 | 9 | G205V | c.614G>T | p.(Gly205Val) | Missense | Possibly damaging (0.908) | Effect (48, 71%) | Protomer destablization | −0.278 | −0.278 | 0.33 | Surface residue | France | rs754802510 | 3.98E−06 | n.i. |
| AKU_00179 | 11 | A267V | c.800C>T | p.(Ala267Val) | Missense | Probably damaging (0.982) | Effect (51, 75%) | Protomer destablization | −0.446 | −0.446 | 0.02 | n.i. | France | n.i. | n.i. | n.i. |
| AKU_00191 | 12 | R330S | c.990G>C | p.(Arg330Ser) | Missense | Probably damaging (0.983) | Effect (91, 95%) | Protomer destablization, Active site disruption | −1.610 | −0.096 | 0.00 | Surface residue; active site | Italy | n.i. | n.i. | n.i. |
| AKU_00184 | 12 | P332R | c.995C>G | p.(Pro332Arg) | Missense | Probably damaging (0.997) | Effect (79, 85%) | Active site disruption | −0.205 | −0.205 | 0.00 | Surface residue; active site | France | n.i. | n.i. | n.i. |
| AKU_00198 | 13 | R336T | c.1007G>C | p.(Arg336Thr) | Missense | Probably damaging (0.998) | Effect (77, 85%) | Hexamer disruption, Active site disruption | 0.506 | −1.589 | 0.00 | n.i. | Ireland | n.i. | n.i. | n.i. |
| AKU_00183 | 13 | I346T | c.1037T>C | p.(Ile346Thr) | Missense | Probably damaging (0.999) | Effect (19, 59%) | Protomer destablization | −0.176 | −0.176 | 0.00 | n.i. | France | rs1299204471 | 7.96E−06 | n.i. |
| AKU_00199 | 13 | R347P | c.1040G>C | p.(Arg347Pro) | Missense | Benign (0.126) | Effect (28, 63%) | Active site disruption | −0.301 | 0.119 | 0.83 | Surface residue | France | n.i. | n.i. | n.i. |
| AKU_00201 | 13 | Y350C | c.1049A>G | p.(Tyr350Cys) | Missense | Probably damaging (1.000) | Effect (75, 85%) | Active site disruption | −0.240 | −0.087 | 0.00 | Active site | Italy | n.i. | n.i. | n.i. |
| AKU_00193 | 9i | ivs9-13T>G | c.650-13T>G | p.(Ala218Cysfs*32) | Splicing (AS) | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Mali | n.i. | n.i. | n.i. |
| AKU_00180 | 8i | ivs8-2A>G | c.550-2A>G | p.(Arg184Glyfs*12) | Splicing (AS) | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Romania | n.i. | n.i. | n.i. |
| AKU_00188 | 10i | ivs10+1G>T | c.774+1G>T | p.(Ala218Cysfs*32) | Splicing (DS) | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Belgium | n.i. | n.i. | n.i. |
| AKU_00192 | 5i | ivs5-11G>A | c.343-11 G>A | p.(?) | Polymorphism | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | Mali | rs143223637 | 0.00144325 | 0.001408776 |
PolyPhen2 and SNAP predictions of the effect of the missense variants on the function of the HGD protein are indicated. The predicted effect of the missense variants upon protomer stability and protein–protein affinity from DUET and mCSM-PPI, respectively, as well as the proposed mechanism leading to loss of activity are also shown. H.10 is a complement of the Shannon entropy value normalized between 0 (corresponding to high conservation) and 1 (high variability). Affected structure refers to the four groups on the basis of their position on the protein structure: core, active site/pore, surface, monomer interface (see also S2 Table). Variants were described based on coding DNA Reference Sequence NM_000187.3 (genomic reference sequence NG_011957.1). DB-ID (variant codes) used in HGD mutation database are indicated. In order to make it easier to recognize variants, we also indicate their brief names as used in AKU scientific community. We have checked both the ExAC and gnomAD databases for the presence of our novel variants (http://gnomad.broadinstitute.org/). For the variant presents in these database rsID, Allele Frequency in gnomAD and Allele Frequency in ExAC are indicated.
n.i. non-identified, n.a. not analyzed