Table 2 Variant pathogenicity prediction.

From: Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

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
1^a	Signature discovery	TET3 (BA); path	p.Phe1072Cys^c; p.Ala1076Thr^c	28.2; 25.9	0; 0	AR, Cpd het	Yes; Yes	Both low TET activityⁱ; CADD; gnomAD; inheritance; in cat domain	None	Both path
2^a	Signature discovery	TET3 (BA); path	p.Val908Leu; p.Val908Leu^c	27	0	AR, Hom	Yes	Low TET activityⁱ; CADD; gnomAD; inheritance; in cat domain	None	Path
3^a	Signature discovery	TET3 (BA); path	p.Val908Leu; p.Val908Leu^c	27	0	AR, Hom	Yes; Yes	Low TET activityⁱ; CADD; gnomAD; inheritance; in cat domain	None	Path
4^a	Signature discovery	TET3 (MA); path	p.His1660Profs*52	NA	0	AD, inherited	Yes	Predicted LOF; gnomAD; inheritance; in cat domain	None	Path
5^a	Signature discovery	TET3 (MA); path	p.His1660Profs*52	NA	0	Unkn	Yes	Predicted LOF; gnomAD; in cat domain	None	Path
6^a	Signature discovery	TET3 (MA^b); path	p.Val1089Met^c; p.Arg752Cys^c	29.1; 23.6	0; 29 (0 hom)	Initially AR; now AD^b	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 ctl^d; NA	Family variant absent (Sanger seq)	NA	NA	NA	NA	NA	NA	Non-path
8	Signature validation	Family ctl^e; NA	Family variant absent (Sanger seq)	NA	NA	NA	NA	NA	NA	Non-path
9	Signature validation	Family ctl^f; NA	Family variant absent (Exome seq)	NA	NA	NA	NA	NA	NA	Non-path
10	Signature validation	Family ctl^g; NA	Family variants absent (Sanger, exome seq)	NA	NA	NA	NA	NA	NA	Non-path
11	Signature validation	TET3 (MA); benign	p.Arg752Cys^c	23.6	29 (0 hom)	Unkn	No	CADD	Nl TET activityⁱ; gnom-AD; not in cat domain	Intermed
12^a	Signature validation	TET3 (MA); path	p.Gln1695*	44	0	AD, de novo	Yes	Predicted LOF; CADD; gnomAD; inheritance; in cat domain	None	Path
13^a	Signature validation	TET3 (MA); path	p.Arg1034*	38	0	AD, de novo	Yes	Predicted LOF; CADD; gnomAD; inheritance; in cat domain	None	Path
14^a	Signature validation	TET3 (MA); path	p.Val1089Met^c	29.1	0	Unkn	Yes	Low TET activityⁱ; CADD; gnomAD; in cat domain.	None	Path
15^a	Signature validation	TET3 (MA); path	p.Val908Leu^c	27	0	Unkn	Yes	Low TET activityⁱ; CADD; gnomAD; in cat domain	None	Path
16^a	Signature validation	TET3 (MA); path	p.Ala1076Thr^c	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
21^a	Testing	TET3 (MA) VUS; unkn	p.Arg911Gln	27.1	0	AD, de novo	Yes	CADD; gnomAD; inheritance; in cat domain	None	Likely path
22^a	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
25^a	Testing	TET3 (MA) VUS; unkn	p.Thr680Tyrfs*26^h	NA	0	Unkn	No	Predicted LOF; gnomAD; inheritance-segregates with phenotype in family	None	Likely path
26^a	Testing	TET3 (MA) VUS; unkn	p.Thr680Tyrfs*26^h	NA	0	AD, inherited	No	Predicted LOF; gnomAD; inheritance-segregates with phenotype in family	None	Likely path
27^a	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.

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Table 2 Variant pathogenicity prediction.

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