Monoallelic variants in genes associated with autosomal recessive PIDs as well as in CLEC16A and TNFRSF13B, identified in patients with rheumatic diseases with persistent hypogammaglobulinaemia and those without
| Pat. ID | Age | Sex | Rheumatic disease | Gene | Ref. seq. transcript | Coding change | Protein change | gnomAD allele freq. | RS-ID | CADD score | MSC–CADD score | PolyPhen2 score | PolyPhen2 pred. | SIFT score | SIFT pred. |
| A: Patients with persistent hypogammaglobulinaemia | |||||||||||||||
| 1 | 57 | F | SpA | RAG1 | NM_000448.ex.2 | c.1346G>A | p.R449K | – | RS4151031 | 18.720 | 1.118 | 0.900 | Possibly damaging | 0.190 | T |
| 2 | 58 | F | SpA | CD79A | NM_001783.ex.2 | c.371G>A | p.R124H | 0.00091180 | – | 33.000 | 22.900 | 0.984 | Probably damaging | NA | NA |
| 3 | 63 | F | SpA | TCF3 | NM_001136139.ex.9 | c.709G>T | p.G237W | – | – | 32.000 | 3.313 | 0.986 | Probably damaging | 0.000 | D |
| 6 | 51 | F | RA | RAD50 | NM_005732.ex.23 | c.3596G>T | p.G1199V | – | – | 32.000 | 0.001 | 1.000 | Possibly damaging | 0.000 | D |
| NBN | NM_001024688.ex.4 | c.37G>A | p.D13N | 0.001858 | RS61753720 | 26.300 | 0.003 | 1.000 | Probably damaging | 0.030 | D | ||||
| 10 | 80 | F | GPA | CLEC16A | NM_001243403.ex.21 | c.2572C>A | p.Q840K | – | – | 22.100 | 3.313 | 0.318 | Benign | 0.000 | D |
| 14 | 53 | F | RA | TCF3 | NM_001136139.ex.5 | c.302A>G | p.K101R | – | RS41275842 | 18.400 | 3.313 | 0.052 | Benign | 0.040 | D |
| 16 | 59 | M | PAN | CLEC16A | NM_015226.ex.22 | c.2675G>A | p.S892N | – | RS72650687 | 19.680 | 3.313 | 0.001 | Benign | 0.000 | D |
| RAG1 | NM_000448.ex.2 | c.1537C>A | p.L513I | – | – | 25.600 | 1.118 | 0.991 | Probably damaging | 0.000 | D | ||||
| 19 | 68 | F | RA | ADA | NM_000022.ex.8 | c.700G>T | p.E234* | – | – | 40.000 | 11.150 | NA | NA | 0.010 | D |
| NBN | NM_001024688.ex.10 | c.1077C>A | p.N277K | – | – | 19.570 | 0.003 | 0.576 | Possibly damaging | 0.010 | D | ||||
| 20 | 66 | F | SjS | TNFRSF13B | NM_012452.ex.4 | c.542C>A | p.A181E | 0.005360 | rs72553883 | 22.800 | 0.027 | 0.395 | Benign | 0.050 | D |
| 21 | 64 | M | SLE | TGFB1 | NM_000660.ex.5 | c.832C>T | p.R278* | – | – | 36.000 | 6.330 | NA | NA | 1.000 | T |
| 22 | 53 | F | RA | STIM1 | NM_003156.ex.12 | c.1928G>A | p.R643H | 0.00097200 | RS140080199 | 29.900 | 14.110 | 0.980 | Probably damaging | 0.000 | D |
| 26 | 69 | F | RA | NBN | NM_001024688.ex.12 | c.1840_1840delA | I614Yfs*43 | – | – | 23.700 | 0.003 | NA | NA | NA | NA |
| 28 | 52 | M | RA | RAG1 | NM_000448.ex.2 | c.2824A>C | p.T942P | – | – | 23.200 | 1.118 | 0.997 | Probably damaging | NA | NA |
| 29 | 53 | F | RA | CLEC16A | NM_001243403.ex.21 | c.2430C>A | p.D810E | 0.00002000 | RS200908373 | 23.900 | 3.313 | 0.292 | Benign | 0.000 | D |
| TNFRSF13B | NM_012452.ex.4 | c.542C>A | p.A181E | 0.005360 | RS72553883 | 22.800 | 0.027 | 0.395 | Benign | 0.050 | D | ||||
| 30 | 69 | F | RA | BLNK | NM_001114094.ex.2 | c.88G>A | p.G30R | 0.0007476 | RS143109144 | 32.000 | 3.313 | 0.973 | Probably damaging | 0.200 | T |
| 31 | 58 | F | SLE | RAD50 | NM_005732.ex.16 | c.2548C>T | p.R850C | 0.00028850 | RS181961360 | 35.000 | 0.001 | 0.724 | Possibly damaging | 0.050 | D |
| 32 | 62 | F | SLE | RELB | NM_006509.ex.1 | c.56C>G | p.P19R | – | – | 24.500 | 3.313 | 0.993 | Probably damaging | 0.000 | D |
| TNFRSF13B | NM_012452.ex.2 | c.198C>A | p.C66* | 0.000008258 | RS144718007 | 36.000 | 0.027 | NA | NA | 1.000 | T | ||||
| 41 | 72 | F | SLE | IGLL1 | NM_020070.ex.3 | c.421_421delT | Y141Ifs*5 | 0.0003378 | – | 24.200 | 3.313 | NA | NA | NA | NA |
| 43 | 47 | F | SpA | TCF3 | NM_001136139.ex.5 | c.302A>G | p.K101R | 0.00964 | RS41275842 | 18.400 | 3.313 | 0.052 | Benign | 0.040 | D |
| 51 | 61 | F | SjS | CD81 | – | IVS5-1 | – | – | – | 24.400 | 12.063 | NA | NA | NA | NA |
| 56 | 28 | M | SLE | TGFB1 | NM_000660.ex.3 | c.593T>C | p.F198S | – | – | 32.000 | 6.330 | 1.000 | Probably damaging | 0.000 | D |
| 58 | 40 | F | RA | RAG1 | NM_000448.ex.2 | c.1346G>A | p.R449K | 0.0036 | – | 18.720 | 1.118 | 0.900 | Possibly damaging | 0.190 | T |
| 62 | 60 | F | SjS | CD79A | NM_021601.ex.5 | c.499G>T | p.G167C | – | – | 22.900 | 22.900 | NA | Possibly damaging | 0.239 | NA |
| 63 | 74 | M | SLE | TGFB1 | NM_000660.ex.7 | c.1147A>T | p.I383F | – | – | 28.200 | 6.330 | 0.000 | Possibly damaging | 0.027 | D |
| B: Patients without hypogammaglobulinaemia | |||||||||||||||
| 65 | 73 | F | SjS | RLTPR | NM_001013838.ex.20 | c.1783_1783delA | p.K595Sfs*11 | 0.000008381 | – | 34.000 | 3.313 | NA | NA | NA | NA |
| 72 | 48 | F | SLE | RLTPR | NM_001317026.ex.36 | c.3914G>T | p.G1305V | – | – | 23.500 | 3.313 | 0.767 | Possibly damaging | 0.030 | D |
| 84 | 52 | F | SLE | NBN | NM_152309.ex.2 | c.84G>T | p.R28S | – | – | 29.000 | 0.003 | 1.000 | Probably damaging | 0.000 | D |
| 85 | 33 | F | SLE | NBN | NM_002485.ex.2 | c.79G>T | p.G27* | – | – | 38.000 | 0.003 | NA | NA | 0.000 | D |
| 89 | 51 | F | SLE | CLEC16A | NM_001243403.ex.21 | c.2524C>T | p.R842C | 0.0002983 | RS199513229 | 35.000 | 3.313 | 0.997 | Probably damaging | 0.000 | D |
| 120 | 52 | F | SjS | CR2 | NM_001877.ex.14 | c.2659G>A | p.V887M | 0.0003997 | RS147451324 | 25.600 | 3.832 | 0.951 | Probably damaging | 0.100 | T |
*substitution - nonsense.
.*, substitution-nonsense; AR, autosomal recessive; CADD, Combined Annotation Dependent Depletion; D, damaging; F, female; freq., frequency; gnomAD, Genome Aggregation Database; GPA, granulomatosis with polyangiitis; Pat. ID, patient identification number; M, male; MSC, Mutation Significance Cut-off; NA, not applicable; PAN, polyarteritis nodosa; PIDs, primary immunodeficiency disorders; PolyPhen2, Polymorphism Phenotyping v2; pred., prediction; RA, rheumatoid arthritis; ref. seq., reference sequence; SIFT, Sorting Intolerance From Tolerance; SjS, Sjögren’s syndrome; SLE, systemic lupus erythematosus; SpA, spondyloarthritis; T, tolerated.