Skip to main content
. 2021 Nov 8;6:92. doi: 10.1038/s41525-021-00256-y

Table 2.

Variant pathogenicity prediction.

Sample Used for Sample type/ Predicted pathogenicity TET3 amino acid changes CADD score GnomAD alleles Inheritance In catalytic domain? Evidence supporting pathogenicity Evidence against pathogenicity Epi-signature pathogenicity prediction
1a Signature discovery TET3 (BA); path p.Phe1072Cysc; p.Ala1076Thrc 28.2; 25.9 0; 0 AR, Cpd het Yes; Yes Both low TET activityi; CADD; gnomAD; inheritance; in cat domain None Both path
2a Signature discovery TET3 (BA); path p.Val908Leu; p.Val908Leuc 27 0 AR, Hom Yes Low TET activityi; CADD; gnomAD; inheritance; in cat domain None Path
3a Signature discovery TET3 (BA); path p.Val908Leu; p.Val908Leuc 27 0 AR, Hom Yes; Yes Low TET activityi; CADD; gnomAD; inheritance; in cat domain None Path
4a Signature discovery TET3 (MA); path p.His1660Profs*52 NA 0 AD, inherited Yes Predicted LOF; gnomAD; inheritance; in cat domain None Path
5a Signature discovery TET3 (MA); path p.His1660Profs*52 NA 0 Unkn Yes Predicted LOF; gnomAD; in cat domain None Path
6a Signature discovery TET3 (MAb); path p.Val1089Metc; p.Arg752Cysc 29.1; 23.6 0; 29 (0 hom) Initially AR; now ADb Yes; No p.Val1089Met low TET activityi; CADD; gnomAD; in cat domain. p.Arg752Cys CADD p.Val1089Met none; p.Arg752Cys nl TET activityi; gnomAD; not in cat domain Path/Intermed
7 Signature validation Family ctld; NA Family variant absent (Sanger seq) NA NA NA NA NA NA Non-path
8 Signature validation Family ctle; NA Family variant absent (Sanger seq) NA NA NA NA NA NA Non-path
9 Signature validation Family ctlf; NA Family variant absent (Exome seq) NA NA NA NA NA NA Non-path
10 Signature validation Family ctlg; NA Family variants absent (Sanger, exome seq) NA NA NA NA NA NA Non-path
11 Signature validation TET3 (MA); benign p.Arg752Cysc 23.6 29 (0 hom) Unkn No CADD Nl TET activityi; gnom-AD; not in cat domain Intermed
12a Signature validation TET3 (MA); path p.Gln1695* 44 0 AD, de novo Yes Predicted LOF; CADD; gnomAD; inheritance; in cat domain None Path
13a Signature validation TET3 (MA); path p.Arg1034* 38 0 AD, de novo Yes Predicted LOF; CADD; gnomAD; inheritance; in cat domain None Path
14a Signature validation TET3 (MA); path p.Val1089Metc 29.1 0 Unkn Yes Low TET activityi; CADD; gnomAD; in cat domain. None Path
15a Signature validation TET3 (MA); path p.Val908Leuc 27 0 Unkn Yes Low TET activityi; CADD; gnomAD; in cat domain None Path
16a Signature validation TET3 (MA); path p.Ala1076Thrc 25.9 0 Unkn Yes Low TET activityi; CADD; gnomAD; in cat domain None Path
17 Testing TET3 (BA) VUS; unkn p.Pro495Ser; p.Val1295Ile 7.9; 19 13 (0 hom); 127 (0hom) AR, Cpd het No; Yes p.Pro495Ser none p.Val1295Ile in cat domain Both CADD; gnomAD; p.Pro495Ser not in cat domain Both likely benign
18 Testing TET3 (BA) VUS; unkn p.Gly1505Arg; p.Trp1746Ser 24.5; 29.3 3 (0 hom); 61 (0 hom) AR, Cpd het Yes; Yes CADDs; both in cat domain GnomAD; both present in unaffected sib Both likely benign
19 Testing TET3 (MA) VUS; unkn p.Pro495Ser 7.9 13 (0 hom) Unkn No None CADD; gnomAD; not in cat domain Likely benign
20 Testing TET3 (MA) VUS; unkn p.Val1295Ile 19 127 (0 hom) Unkn Yes In cat domain CADD; gnomAD Likely benign
21a Testing TET3 (MA) VUS; unkn p.Arg911Gln 27.1 0 AD, de novo Yes CADD; gnomAD; inheritance; in cat domain None Likely path
22a Testing TET3 (MA) VUS; unkn p.Arg1683His 31 0 AD, de novo Yes CADD; gnomAD; inheritance; in cat domain None Likely path
23 Testing TET3 (MA) VUS; unkn p.Gly1505Arg 24.5 3 (0 hom) Unkn Yes CADD; in cat domain GnomAD; this variant, p.Trp1746Ser in unaffected sib Likely benign
24 Testing TET3 (MA) VUS; unkn p.Trp1746Ser 29.3 61 (0 hom) Unkn Yes CADD; in cat domain GnomAD; this variant, p.Gly1505Arg in unaffected sib Likely benign
25a Testing TET3 (MA) VUS; unkn p.Thr680Tyrfs*26h NA 0 Unkn No Predicted LOF; gnomAD; inheritance-segregates with phenotype in family None Likely path
26a Testing TET3 (MA) VUS; unkn p.Thr680Tyrfs*26h NA 0 AD, inherited No Predicted LOF; gnomAD; inheritance-segregates with phenotype in family None Likely path
27a Testing Episign screen; unkn p.Cys246* 34 0 AD, inherited No Predicted LOF; CADD; gnomAD; inherited from mosaic mother None Likely path

BA bi-allelic, MA mono-allelic, path pathogenic, non-path non-pathogenic, NA not applicable, unkn unknown, AR autosomal recessive, Cpd het compound heterozygote, Hom homozygous, AD autosomal dominant, LOF loss-of-function, cat catalytic, nl normal, seq sequencing, sib sibling, CADD score combined annotation-dependent depletion score (https://cadd.gs.washington.edu/); gnomAD browser is at https://gnomad.broadinstitute.org/.

aTET3-deficient pathogenic samples used to identify the final DNA methylation episignature.

bConsidered mono-allelic because only the c.3265G>A (p.Val1089Met) variant reduced catalytic activity in vitro, suggesting pathogenicity; c.2254C>T (p.Arg752Cys) did not reduce catalytic activity in vitro, suggesting non-pathogenicity (ref. 8).

cVariants previously tested in our in vitro assay (ref. 8).

dUnaffected daughter of Sample 5 and sister of Sample 4.

eUnaffected son of 25 and brother of 26.

fUnaffected mother of Sample 4.

gUnaffected sister of Sample 6 and daughter of Samples 11 and 14.

hPreviously considered VUS because mother was not thought to be affected; upon further evaluation, she was noted to be affected (see text for details).

iTET activity based on in vitro assay performed and reported in reference8.