Table 1.
Variants detected within the genes associated with MO and in silico prediction of their pathogenicity
| Gene | Chromosome | Position (GRCh37) | SNP ID | Change in gene | Change in protein | Transcript | QGP allele frequency* | gnomAD allele frequency | CADD | SIFT | PolyPhen 2 | Mutation Taster | SNPs&GO | HGMD class | HGMD phenotype | ACMG manual** | ACMG class |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ADCY3 | 2 | 25,059,790 | rs115329263 | C.1658C>T | P.A553V | 0.009343 | 0.0001704 | 14.97 | Tolerated | Benign | Polymorphism | Neutral | − | − | PM1 | Uncertain significance (cool) | |
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ENST00000260600 |
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| 2 | 25,141,368 | rs143034828 | c.489C>G | P.H163Q | 0.00496 | 0.000003984 | 13.48 | Tolerated | Probably damaging | Polymorphism | Neutral | −A4265 | PM1/BP4 | Uncertain significance (cool) | |||
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| MC3R | 20 | 54,824,819 | rs1481948431 | c.920G>A | p.Arg307His | ENST00000243911 | 0.00102249 | 0.000003997 | 26.7 | Deleterious | Probably damaging | Disease causing | − | − | PM2/PP3 | Uncertain significance (tepid) | |
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| MC4R | 18 | 58,039,098 | rs1555691402 | c.485C>T | P.T1621 | ENST00000299766 | 0.0011576 | 27.1 | Deleterious | Probably damaging | Disease causing | Disease | DM | Early onset obesity | PM1/PM2 | Uncertain significance (warm) | |
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| MRAP2 | 6 | 84,765,081 | rs760845706 | c.44C>T | p.S15L | 0.0001654 | 0.00006373 | 23.4 | Deleterious | Benign | Polymorphism | Neutral | − | − | PM2 | Uncertain significance (cool) | |
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| 6 | 84,799,133 | rs1054400375 | c.551T>C | P.I184T | ENST00000257776 | 0.000082686 | − | 23.2 | Deleterious | Benign | Disease causing | Neutral | − | − | PM2 | Uncertain significance (cool) | |
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| 6 | 84,798,925 | rs368589399 | C.343C>G | P.L115V | 0.000413428 | 0.0001034 | 23 | Deleterious | Benign | Disease causing | Neutral | DM | Severe early onset obesity | BP4 | Uncertain significance (ice cold) | ||
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| PCSK1 | 5 | 95,761,591 | rs748072514 | c.329G>A | p.R110H | 0.000082713 | 0.00001770 | 28.3 | Deleterious | Probably damaging | Disease causing | Disease | − | − | PM1/PP3 | Uncertain significance (tepid) | |
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| 5 | 95,735,682 | rs1026383684 | C.14050A | P.V4691 | ENST00000311106 | 0.00239868 | 0.00002122 | 17.55 | Tolerated | Benign | Polymorphism | Neutral | − | − | PM1 | Uncertain significance (cool) | |
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| 5 | 95,728,961 | rs567748971 | c.2006G>T | P.R669L | 0.000578991 | 0.000003983 | 23.2 | Deleterious | Benign | Polymorphism | Neutral | − | − | PM2 | Uncertain significance (cool) | ||
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| POMC | 2 | 25,384,596 | rs28932470 | c.158A>G | p.D53G | ENST00000264708 | 0.00124 | 0.001007 | 15.53 | Tolerated | Benign | Disease causing | Disease | − | PM1/BP1 | Likely benign | |
Based on 6,047 genomes.
ACMG classification key. Criteria for pathogenicity. PM1 (Moderate): Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM2 (Moderate): Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or ExAC. PP3 (Supporting): Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Criteria for a benign nature: BP1 (Supporting): Missense variant in a gene for which primarily truncating variants are known to cause disease. BP4 (Supporting): Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).