Table 1.
Variants in CYP7A1, LDLRAP1 and LRP6. The pathogenicity of the variants was evaluated using Varsome, PolyPhen2, Provean, ClinVar, CADD score and Splice AI.
| Gene | c.notation p.notation |
rs Number | Pathway | GTEx-TPM_Liver # | gnomAD (Total) * |
gnomAD (ENF) * | FREX ** | Varsome *** | PolyPhen2 | Provean † | ClinVar | CADD Score ‡ | Splice AI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
CYP7A1 (NM_000780) |
c.38C > T p.(Ala13Val) |
rs147162838 | Bile acid and bile salt metabolism | 2.612 | 0.181% (512/282,726) |
0.35% (451/129,062) |
0. | LB | B | N (−0.189) |
LB/VUS | 7.125 | No-consq (0) |
| c.1039G > A p.(Asp347Asn) |
rs8192875 | 0.274% (776/282,802) |
0.019% (25/129,150) |
… | LB | PD | D (−0.2990) |
… | 33 | Donor gain (0.48) | |||
| c.1192C > G p.(Pro398Ala) |
rs142708991 | 0.336% (951/282,868) |
0.43% (555/129,184) |
0.0871% | LB | PD | D (−7.559) |
LB | 25.1 | No-consq (0) |
|||
|
LDLRAP1 (NM_015627) |
c.603dupC p.(Ser202LeufsTer19) |
rs781585299 | Clathrin-mediated endocytosis | 112.23 | … | … | … | P | … | … | P | … | … |
| c.604_605delTCinsCA p.(Ser202His) |
rs386629678 | … | … | … | LB | PD | N (−2.072) |
LB | … | … | |||
|
LRP6 (NM_002336) |
c.2915A > G p.(Tyr972Cys) |
rs772441071 | Vesicle-mediated transport | 9.662 | 0.001193% (3/251,364) |
0.002640% (3/113,656) |
… | VUS | PD | D (−7.227) |
… | 26.9 | Acceptor gain (0.04) |
| c.4144G > T p.(Val1382Phe) |
rs139480047 | 0.08379% (237/282,856) |
0.1061% (137/129,164) |
0.261% | B | B | N (−1.246) |
LB | 22.3 | Donor gain (0.02) | |||
| c.4436C > T p.(Thr1479Ile) |
rs144175121 | 0.02263% (64/282,836) |
0.04335% (56/129,168) |
… | B | B | N (−1.906) |
… | 23.3 | No-consq (0) |
|||
| c.4835C > T p.(Ser1612Phe) |
… | 0.0008097% (2/247,016) |
0% (0/111,624) |
… | VUS | PD | D (−2.879) |
… | 29.4 | Donor gain (0.02) |
# Gene expression in the liver, from the Genotype Tissue Expression database (GTEx). TPM: transcripts per million. * Allele frequency, from the Genome Aggregation Database (gnomAD): allele count/allele number in the general population and in the European non-Finnish (ENF). ** Allele frequency from the French Exome Project database. *** Varsome tool according to the ACMG guidelines [33]. † Provean: variant with a score of ≤−2.5 is considered “deleterious” and with a score of >−2.5 is considered “neutral”. ‡ CADD score ≥ 20 indicates that the variant is predicted to be among the top 1% of the most deleterious substitutions in the human genome, and a score of ≥30 indicates that the variant is predicted to be among the top 0.1% of the most deleterious substitutions in the human genome. N: neutral, LB: likely benign, B: benign, VUS: variant of unknown significance, PD: probably damaging, D: deleterious, P: pathogenic.