Table 1.
A2ML1 Variants Identified in Multi-ethnic Families and Probands with Otitis Media
| Cohort-Patient ID |
hg19 chr12 Coordinate |
Variant (NM_144670.5)† | Control MAF‡ |
Protein Domain |
CADD | Mutation Taster | PolyPhen-2 HumDiv |
PROVEAN | SIFT | Mutation Assessor |
|---|---|---|---|---|---|---|---|---|---|---|
| I. Pathogenic/likely pathogenic | ||||||||||
| CIFIL-11 | 8975257 | c.10C>T (p.(Gln4*)) | 0 | MG1 | 35.0 | D(NMD) | -- | -- | -- | -- |
| UTMB-1039 | 8990070 | c.763C>T (p.(Gln255*)) | 0 | MG3 | 35.0 | D(NMD) | -- | -- | -- | -- |
| IPOM, UTMB-959/969/970 | 9004827 | c.2478_2485dupGGCTAAAT (p.(Ser829Trpfs*)) | 0 | MG7 | -- | D(NMD) | -- | -- | -- | -- |
| UTMB-1031 | 9009825 | c.2914G>T (p.(Glu972*)) | 0 | CUB/TED | 44.0 | D(NMD) | -- | -- | -- | -- |
| IPOM, CIFIL-21 | 9020954 | c.4061+1G>C | 0 | RBD | 25.7 | D | -- | -- | -- | -- |
| II. Variants of unknown significance | ||||||||||
| UTMB-1031 | 8975879 | c.164C>T (p.(Thr55Ile) | 0 | MG1 | 19.6 | P | PoD | D | D | M |
| UTMB-1178, UMN-123 | 8990963 | c.887T>C (p.(Val296Ala)) | 0.0009 | MG3 | 22.5 | P | B | D | D | M |
| UHF-269 | 8991701 | c.971–8C>T | 0.0006 | MG3 | 13.9 | D | -- | -- | -- | -- |
| UTMB-1017 | 8991805 | c.lO67C>G (p.(Pro356Arg)) | 0 | MG4 | 25.0 | P | PoD | D | D | M |
| UHF-101 | 8995789 | c.1308A>C (p.(Gln436His)) | 0.00005 | MG4 | 15.4 | P | B | N | T | M |
| UTMB-1026 | 8998818 | c.1683G>C (p.(Gln561His)) | 0 | MG6 | 33.0 | D | PoD | D | D | M |
| CIFIL-14 | 9001494 | c.2012T>C (p.(Leu671Pro)) | 0 | MG6/BRD | 13.3 | P | B | D | D/r | L |
| UTMB-998 | 9002825 | c.2189G>A (p.(Arg730His) | 0.00003 | MG6 | 21.3 | P | B | D | T/D | L |
| UHF-254/255 | 9002833 | c.2197T>C (p.(Phe733Leu)) | 0.004 | MG6 | 23.0 | D | B | D | T/D | L |
| UTMB-1027 | 9002864 | c.2228C>T (p.(Pro743Leu)) | 0 | MG6 | 23.4 | P | B | D | T | L |
| CIFIL-11 | 9004474 | c.2329G>A (p.(Gly777Arg)) | 0 | MG7 | 23.3 | D | PrD | D | D | H |
| UTMB-1031 | 9004573 | c.2428G>A (p.(Ala810Thr)) | 0 | MG7 | 25.2 | D | PrD | D | D | H |
| UTMB-1019 | 9004887 | c.2545G>T (p.(Asp849Tyr)) | 0 | MG7 | 15.6 | P | PoD | D | D | M |
| UTMB-1030 | 9006810 | c.2677C>T (p.(Arg893*)) | 0.00009 | MG7 | 34.0 | D(NMD) | -- | -- | -- | -- |
| 7 UHF families | 9007368 | c.2713–8C>A§ | 0.013 | MG7 | 4.8 | D | -- | -- | -- | -- |
| UTMB-1018 | 9009882 | c.2971G>C (p.(Ala991Pro)) | 0 | CUB/TED | 20.8 | P | B | N | D | L |
| UTMB-971 | 9009912 | c.3001C>T (p.(Arg1001Trp)) | 0 | CUB/TED | 24.5 | P | PrD | D | D | M |
| UTMB-959 | 9013882 | c.3491C>T (p.(Ala1164Val)) | 0 | CUB/TED | 27.5 | D | PrD | D | D | M |
| PKOM-10/15 | 9016563 | c.3676_3677delGC (p.(Ala1226Glnfs*34)) | 0.07 | CUB/TED | -- | P(NMD) | -- | -- | -- | -- |
| UTMB-1027 | 9027091 | c.4292C>T (p.(Ala1431Val)) | 0 | RBD | 25.6 | D | PrD | D | D | L |
Abbreviations: BRD, bait-region domain; CADD, Combined Annotation Dependent Depletion; CIFIL, Filipino cochlear implantee; CUB, complement protein subcomponent C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1 domain; IPOM, indigenous Filipino cohort; MAF, minor allele frequency; MG, macroglobulin domain; RBD, receptor-binding domain; TED, thiol ester-containing domain; UHF, Finnish cohort; UMN, Minnesota cohort; UTMB, Texas cohort. MutationTaster: D, disease-causing; NMD, nonsense-mediated decay; P, polymorphism. PolyPhen-2: PrD, probably damaging; PoD, possibly damaging; B, benign. PROVEAN: D, deleterious; N, neutral. SIFT: D, deleterious; T, tolerated (“/” denotes multiple predictions depending on isoform). MutationAssessor: H, high; M, medium; L, low.
Novel variants are in bold font. Known variants were previously reported in Santos-Cortez et al. 2015.
For CIFIL and IPOM, control MAF is from the Cebu Longitudinal Health and Nutrition Survey. For UHF, UMN and PKOM, control MAF is from gnomAD Finnish, non-Finnish European and South Asian, respectively. For UTMB, control MAF is either from gnomAD non-Finnish European or Latino populations depending on self-reported ethnicity. UTMB IDs 959, 1030, 1031, 1039 and 1178 are Hispanic while the rest of UTMB IDs are non-Hispanic White. In some cases the gnomAD MAF in another population is higher, e.g. the c.2677C>T (p.(Arg893*)) variant has Latino MAF 0.00009 but has African and non-Finnish European MAF=0.0002.
Eight individuals with exome data from seven Finnish families carry the c.2713–8C>A variant (Supp. Fig. S1). From the exome data two common SNPs namely rs73037000 (chr12:8987285G>A) and rs1860967 (chr12:9013755C>T) flank the c.2713–8C>A variant, which comprise a short 26,470-bp haplotype found in all eight carriers. However four carriers have various common or low-frequency variants within the haplotype, suggesting that this haplotype is very old and multiple recombinations have occurred within the region.