Table 1.
Candidate pathogenic DEAF1 variants in SAND and NLS domains identified through clinical exome sequencing in this study
| Variant | Position | Variant type | Zygosity | Allele frequency Ø | Putative impact § | Functional evidence |
Assessment | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||||||||
| DNA alteration | Protein alteration† |
location | Protein domain |
De novo status * |
Novelty | ID referrals to CES |
ExAC | 1000 genome |
ESP 5400 |
PolyPhen2 (HumDiv / HumVar) |
SIFT | ACMG† | |||
|
|
|
|
|
|
|||||||||||
| c.634G>A | p.Gly212Ser | Exon 4 | SAND | De novo | Novel | Het | 8.24E-05 | 0 | 0 | 0 | PD 1.000/PD 0.995 | D 0.01 | PS2 | This study | D |
| c.676C>T | p.Arg226Trp | Exon 5 | SAND | Inherited | [Faqeih, 2014; Gund, 2016] | Hom | 1.65E-04 | 8.28 E-06 | 0 | 0 | PD 1.000/PD 0.999 | D 0.00 | PM1 | This study | D |
| c.700T>A | p.Trp234Arg | Exon 5 | SAND | De novo | [Berger, 2017] | Het | 0 # | 0 | 0 | 0 | PD 1.000/PD 1.000 | D 0.00 | PS2 | This study | D |
| c.737G>C | p.Arg246Thr | Exon 5 | SAND | De novo | [Wenge, 2017] | Het | 8.24E-05 | 0 | 0 | 0 | PD 0.999/PD 0.997 | D 0.01 | PS2 | This study | D |
| c.791A>C | p.Gln264Pro | Exon 5 | SAND | De novo | [Rauch, 2012; Vulto, 2014] | Het | 8.24E-05 | 0 | 0 | 0 | PD 0.999/PD 0.972 | D 0.01 | PS2 | [Rauch, 2012; Vulto, 2014] | D |
| c.913_915del | p.Lys305del | Exon 7 | NLS | De novo | Novel | Het | 8.24E-05 | 0 | 0 | 0 | N.A. | N.A. | PS2 | This study | D |
The DNA variant numbering system used in this study is based on human DEAF1 cDNA sequence (RefSeq NM_021008.3). Nucleotide numbering uses +1 as the A of the ATG translation initiation codon in the reference sequence, with the initiation codon as codon 1.
Verified by Sanger sequencing.
Listed minor allele frequencies are from the ExAC browser (exac.broadinstitute.org), 1000 Genomes Project (www.1000genomes.org), and ESP5400 data of the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (http://evs.gs.washington.edu/EVS)
Predicted by Polyphen2 (http://genetics.bwh.harvard.edu/pph2/index.shtml) and SIFT (http://sift.jcvi.org/), variant function interpreted according to the guidelines from the American College of Medical Genetics and Genomics (ACMG)31. According to the ACMG guidelines, PS2 indicates “De novo (both maternity and paternity confirmed) in a patient with the disease and no family history” and PM1 indicates “ Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation”.
Patient was found in a cohort of 6 patients with SMS-like phenotypes, 1 sibling, and 12 parents
Abbreviations: PD (Probably damaging), D (Damaging), N.A. (not available), Het (heterozygote), Hom (homozygote)