Table 2.
Qualifying Variants among the Top Three Pulmonary Fibrosis Genes
| Patient | Sex | Family History | Fibrosis Phenotype | Gene | Chromosomal Coordinates GRCh37/hg19 (rs refsnp) | HGVS Identifier (Protein) | Effect | ExAC Genotype Distribution | Literature Phenotype | OMIM Variant Identifier | Qualifying Model* | GERP | CADD | PolyPhen-2 HumDiv |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| pf316 | M | N | IPF | TERT | chr5:g.1279426G>A (rs199422297) | NP_937983.2 p.Pro704Ser | Missense | 29,430/0/0 | Dyskeratosis congenita AD | 0.0014 | Primary | 2.47 | 5.96 | 0.998 |
| pf350 | M | Y | IPF | |||||||||||
| pf1132 | F | N | IPF | |||||||||||
| pf1180 | F | Y | IPF | |||||||||||
| pf65 | M | N | IPF | TERT | chr5:g.1278817C>T (rs727503468) | NP_937983.2 p.Arg742His | Missense | 60,706/0/0 | — | — | Primary | 3.74 | 24.3 | 0.987 |
| pf1318 | M | N | IPF | TERT | chr5:g.1279547G>C | NP_937983.2 p.Ser663Arg | Missense | 10,193/0/0 | — | — | Primary | −5.1 | 10.59 | 0.998 |
| pf132 | F | Y | CTD UIP | TERT | chr5:g.1254522G>A | NP_937983.2 p.Arg1086Cys | Missense | 59,219/0/0 | — | — | Primary | −6.21 | 17.94 | 0.999 |
| pf238 | M | N | IPF | TERT | chr5:g.1279455A>T | NP_937983.2 p.Val694Glu | Missense | 28,149/0/0 | — | — | Primary | 0.97 | 23.5 | 1 |
| pf514 | M | N | IPF | TERT | chr5:g.1264550G>A | NP_937983.2 p.Arg938Trp | Missense | 58,867/0/0 | — | — | Primary | 3.42 | 33 | 1 |
| pf681 | M | N | IPF | TERT | chr5:g.1279467C>G | NP_937983.2 p.Trp690Ser | Missense | 25,430/0/0 | — | — | Primary | 4.67 | 25.9 | 1 |
| pf717 | M | N | IPF | TERT | chr5:g.1280338C>G | NP_937983.2 p.Gly629Arg | Missense | 60,609/0/0 | — | — | Primary | 4.48 | 25.4 | 1 |
| pf1110 | F | Y | IPF | TERT | chr5:g.1266613T>C | NP_937983.2 p.Thr874Ala | Missense | 56,038/0/0 | — | — | Primary | 3.99 | 23.8 | 1 |
| pfB103 | F | N | IPF | TERT | chr5:g.1280455T>C | NM_198253.2 c.1770-2A>G | Splice site acceptor | 60,075/0/0 | — | — | Primary and LoF 0.1% | — | 16.51 | — |
| pf166 | M | Y | IPF | RTEL1 | chr20:g.62324564C>T (rs398123017) | NP_116575.3 p.Arg998Ter | Stop gain | 59,955/2/0 | Dyskeratosis congenita AR | 0.0004 | LoF 0.1% | — | 37 | — |
| pf941 | M | N | IPF | |||||||||||
| pf1532 | M | N | IPF | |||||||||||
| pf1226 | F | Y | IPF | RTEL1 | chr20:g.62324600C>T (rs373740199) | NP_116575.3 p.Arg1010Ter | Stop gain | 59,848/10/0 | Dyskeratosis congenita AD | 0.0012 | LoF 0.1% | — | 35 | — |
| pf53 | F | N | IPF | RTEL1 | chr20:g.62320919A>AC | NP_116575.3 p.Arg675ThrfsTer15 | Frameshift | 58,946/0/0 | — | — | Primary and LoF 0.1% | — | 28.4 | — |
| pf191 | M | N | IPF | RTEL1 | chr20:g.62321438A>G | NM_032957.4 c.2214-2A>G | Splice site acceptor | 59,613/0/0 | — | — | Primary and LoF 0.1% | — | 22.2 | — |
| pf249 | M | Y | IPF | RTEL1 | chr20:g.62321112G>A | NP_116575.3 p.Gly703Arg | Missense | 58,909/0/0 | — | — | Primary | 4.61 | 27.5 | 1 |
| pf304 | M | N | IPF | RTEL1 | chr20:g.62321483C>T | NP_116575.3 p.Arg753Cys | Missense | 59,716/0/0 | — | — | Primary | 4.57 | 29.7 | 1 |
| pf1191 | M | N | IPF | |||||||||||
| pf1576 | M | N | IPF | RTEL1 | chr20:g.62321477T>C | NP_116575.3 p.Trp751Arg | Missense | 59,716/0/0 | — | — | Primary | 4.57 | 24.9 | 1 |
| pf143 | F | Y | Fibrosing NSIP | PARN | chr16:g.14698077G>A (rs760506977) | NP_002573.1 p.Arg237Ter | Stop gain | 27,816/1/0 | — | — | LoF 0.1% | — | 38 | — |
| pf244 | M | N | IPF | PARN | chr16:g.14704526G>A (rs876661305) | NP_002573.1 p.Gln177Ter | Stop gain | 59,377/0/0 | Pulmonary fibrosis AD | 0.0006 | Primary and LoF 0.1% | — | 37 | — |
| pfB467 | M | N | IPF | |||||||||||
| pf1099 | M | N | IPF | |||||||||||
| pf1311 | M | N | IPF | |||||||||||
| pf566 | M | N | IPF | PARN | chr16:g.14540858CCT>C | NP_002573.1 p.Glu585AspfsTer5 | Frameshift | 5,9377/0/0 | — | — | Primary and LoF 0.1% | — | 28.6 | — |
| pf1495 | M | N | IPF | PARN | chr16:g.14676110C>A | NP_002573.1 p.Glu374Ter | Stop gain | 59,377/0/0 | — | — | Primary and LoF 0.1% | — | 43 | — |
| pf1466 | M | N | IPF | PARN | chr16:g.14647946G>C | NP_002573.1 p.Leu461Val | Missense | 58,345/0/0 | — | — | Primary | 5.93 | 27.7 | 0.994 |
Definition of abbreviations: AD = autosomal dominant; AR = autosomal recessive; CADD = Combined Annotation Dependent Depletion score; CTD UIP = usual interstitial pneumonia associated with connective tissue disease; ExAC = Exome Aggregation Consortium; GERP = Genomic Evolutionary Rate Profiling score; HGVS = Human Genome Variation Society; IPF = idiopathic pulmonary fibrosis; LoF = loss of function; N = no; NSIP = nonspecific interstitial pneumonia; OMIM = Online Mendelian Inheritance in Man database; PolyPhen-2 = Polymorphism Phenotyping version 2; Y = yes.
The ExAC genotype distribution reflects the corresponding homozygous reference, heterozygous variant, and homozygous variant counts found in the ExAC browser of up to 60,706 samples. Annotations for qualifying variants derived from models other than the primary and LoF model are available in Table E9 in the online supplement. Refsnp (rs) single-nucleotide polymorphism identifiers are provided where available. A higher-resolution relatedness screen confirmed that no two cases carrying one of the recurring TERT, RTEL1, or PARN qualifying variants shared more than 1% of their protein-coding variants at a minor allele frequency less than or equal to 1% (Table E10).
See Table E4 in the online supplement for details.