Table 3

Novel, unreportable diagnoses identified via reverse phenotyping research diagnostic workflow

Research ID	Recruitment category	Gene	Variant zygosity	Consequence	HGVSc	HGVSp	gnomAD AF	100K MAF	SIFT	PolyPhen	CADD	PubMed	ClinVar listing	Segregation	# of key features
52	Intellectual disability	ALMS1	Het	Mis	NM_015120.4:c.7738A>T	NP_055935.4:p.Ile2580Phe	4.01E-06	0.00009997	Delet	Ben	22.5	Abs	Abs	Mat	0M, 2m
52	Intellectual disability	ALMS1	Het	Mis	NM_015120.4:c.346C>T	NP_055935.4:p.His116Tyr	2.41E-05	0.00019994	Delet	Ben	16.05	Abs	Abs	Pat	0M, 2m
59	Hereditary spastic paraplegia	BBS1	Het	Mis	NM_024649.5:c.235G>A	NP_078925.3:p.Glu79Lys	0.000756	0.00120728	Delet	Poss_dam	23.8		VUS	Unk	0M, 0m
59	Hereditary spastic paraplegia	BBS1	Het	Mis	NM_024649.5:c.1714G>T	NP_078925.3:p.Gly572Cys	–	1.27E-05	Delet	Prob_dam	32		Abs	Unk	0M, 0m
60	Primary immunodeficiency	CEP290	Het	FS	NM_025114.4:c.6154_6161del	NP_079390.3:p.Asp2052LeufsTer17	0	1.27E-05				Abs	Abs	Unk	0M, 0m
60	Primary immunodeficiency	CEP290	Het	FS	NM_025114.4:c.7412_7415del	NP_079390.3:p.Glu2471ValfsTer13	0	1.91E-05				Abs	Abs	Unk	0M, 0m
61	Primary lymphoedema	CEP290	Het	SG	NM_025114.4:c.7048C>T	NP_079390.3:p.Gln2350Ter	1.90E-05	1.91E-05				Abs	lik_path	Unk	0M, 0m
61	Primary lymphoedema	CEP290	Het	Mis	NM_025114.4:c.4063C>T	NP_079390.3:p.Arg1355Cys	4.97E-05	9.53E-05	Delet	Prob_dam	32	Abs	VUS	Unk	0M, 0m
64	Limb-girdle muscular dystrophy	CEP290	Hom	Mis	NM_025114.4:c.4805C>T	NP_079390.3:p.Thr1602Met	0.000226	0.00027958	Delet	Poss_dam	27.7	Abs	lik_path, VUS	Unk	0M, 0m
65	Undiagnosed monogenic disorders	CEP290	Het	Mis	NM_025114.4:c.5909C>A	NP_079390.3:p.Thr1970Asn	0	1.27E-05	Delet	Prob_dam	25.6	Abs	Abs	Unk	0M, 0m
65	Undiagnosed monogenic disorders	CEP290	Het	SG, FS	NM_025114.4:c.7283_7286dup	NP_079390.3:p.Tyr2429Ter	2.11E-05	2.54E-05				Abs	Abs	Unk	0M, 0m
68	Early onset dementia	CEP290	Het	Mis	NM_025114.4:c.31A>G	NP_079390.3:p.Met11Val	7.72E-05	6.35E-06	Delet	Ben	23.2	–	VUS	Unk	0M, 0m
68	Early onset dementia	CEP290	Het	Mis	NM_025114.4:c.2447G>A	NP_079390.3:p.Arg816His	3.13E-05	6.35E-05	Delet	Prob_dam	26.4	–	VUS	Unk	0M, 0m
69	Epilepsy plus other features	CEP290	Het	Mis	NM_025114.4:c.2446C>T	NP_079390.3:p.Arg816Cys	5.00E-05	2.54E-05	Delet	Prob_dam	32	25 741 868	VUS	Unk	0M, 0m
69	Epilepsy plus other features	CEP290	Het	Mis	NM_025114.4:c.4741C>T	NP_079390.3:p.Leu1581Phe	1.32E-05	1.27E-05	Delet	Poss_dam	25.1	25 741 868	VUS	Unk	0M, 0m
71	Hereditary ataxia	DYNC2H1	Het	Mis	NM_001377.3:c.10142C>T	NP_001368.2:p.Pro3381Leu	3.62E-05	1.00E-04	Delet	Prob_dam	31	Abs	lik_path, path	Unk	0M, 0m
71	Hereditary ataxia	DYNC2H1	Het	Mis	NM_001377.3:c.3419G>T	NP_001368.2:p.Gly1140Val	0.0003938	0.00044987	Delet	Ben	23.2	Abs	VUS	Unk	0M, 0m
72	Early onset dementia	OFD1 (♀)	Het	Spl_A	NM_003611.3:c.936–1G>A	–	0	6.35E-06				Abs	Abs	Unk	0M, 0m
73	Early onset dystonia	OFD1 (♀)	Het	FS	NM_003611.3:c.1911del	NP_003602.1:p.Glu637AspfsTer29	0	6.35E-06				Abs	Abs	Unk	0M, 0m

Abs, absent; ACMG, American College of Medical Genetics and Genomics; AF, allele frequency; CADD, Combined Annotation Dependent Depletion; F, female; FS, frameshift; Hemi, hemizygous; Het, heterozygous; HGVSc, Human Genome Variation Society coding; HGVSp, Human Genome Variation Society protein; Hom, homozygous; Intr, intronic; 100K, 100 000 Genomes Project; Lik_path, likely pathogenic; M, male; M, major clinical feature; m, minor clinical feature; MAF, maximum allele frequency; Mat, maternal; Mis, missense; Pat, paternal; Path, pathogenic; Spl Reg, splice region; SG, stop gain; SL, start loss; Spl A, splice acceptor; SV, structural variant; Syn, synonymous; Unk, unknown; VUS, variant of uncertain significance.