Ultra-rare and rare variants identified in 2 families each, sorted by MAF
| Position change | Gene* | Location/ type of variant | MAF, % | CADD | ACMG classification (ACMG criteria met) | Fam, P(obs)† |
|---|---|---|---|---|---|---|
| 19:53803962 G/A | NLRP12 | Exonic/missense | 0.01 | 23.3 | Likely benign (BS2) | G, I, 0.000211 |
| 5:76482747 A/C | IQGAP2 | Intronic | 0.08 | 15.9 | Benign (BS1, BS2) | E, X, 0.000842 |
| 4:109086168 T/A | COL25A1 | Intronic | 0.10 | 19.0 | Likely benign (BS1) | H, J, 0.004208 |
| 1:223300619 G/A | SUSD4 | Intronic | 0.20 | 16.4 | VUS with benign evidence (BP4) | J, X, 0.008415 |
| 12:120368947 C/A | MSI1 | Intronic | 0.33 | 16.4 | Benign (BS1, BS2, BP4) | J, R, 0.013885 |
| 1:31727178 G/A | ADGRB2 | 3′ UTR | 0.60 | 13.2 | Benign (BS1, BS2) | B, G, 0.003151 |
| 12:10723010 G/T | YBX3 | Exonic/missense | 0.72 | 22.2 | Likely benign (BS1, BP4) | J, T, 0.030294 |
| 11:111020375 C/A | AP003973.4 | Intergenic | 0.73 | 14.0 | Benign (BS1, BS2, BP4, BP7) | E, S, 0.007679 |
| 6:101375096 A/G | GRIK2 | Intronic | 0.73 | 20.5 | Benign (BS1, BS2) | D, G, 0.003833 |
| 12:97272797 T/A | LINC02409 | Intronic/splice | 0.75 | 14.7 | Benign (BA1, BP4, BP7) | G, X, 0.031556 |
| 7:713068 C/T | PRKAR1B | 5′ UTR | 0.75 | 10.5 | Benign (BS1, BS2, BP4) | A, J, 0.015778 |
| 1:121379326 G/A | SRGAP2C | Intronic | 0.91 | 15.5 | Benign (BA1, BP4) | J, X, 0.038288 |
| 10:74875378 T/C | KAT6B | Intronic | 0.95 | 11.0 | Benign (BS1, BS2, BP4) | J, X, 0.039972 |
| 6:17649263 G/A | NUP153 | Exonic/missense | 0.99 | 27.7 | Benign (BS1, BS2, BP1, PP3) | C, J, 0.002599 |
ACMG = American College of Medical Genetics and Genomics; CADD = combined annotation dependent depletion; MAF = minor allele frequency; UTR = untranslated region; VUS = variant of unknown significance.
↵* Several genes had more than 1 ultra-rare variant with putatively severe consequences. Seven genes (BSN, FLG-AS1, FN1, NLRP12, PTPN14, RBL2, and SNX19) had 2 missense variants each, with a third variant in BSN located in 3′ UTR. Three out of 4 variants located in TTN were missense. Eight genes had 1 missense and 1 3′ UTR or 5′ UTR variant: AC046130.1, GAPVD1, IGSF3, NOL4L, ROBO2, SEMA4A, TMEM63B, TPRG1.
↵† P(obs) – probability of cosegregation of a particular variant in a given 2 families, Bonferroni corrected to 136 possible pairs of families: P(obs) = P(seg_fam1) × P(anyvar) × P(seg_fam2) × P(var) × 136. P(any var) = 0.99 – probability of a variant in family 1 with CADD > 10 and MAF < 0.01. P(var) = MAF – the probability of observing the particular variant in the second family P(var).