Table 4 Details of pipeline performance for 18 candidate molecular diagnoses for previously unsolved cases based on Illumina TruSight or Ion Torrent sequencing as indicated. These 18 candidate variants were considered of immediate clinical relevance upon clinical review.

From: A flexible computational pipeline for research analyses of unsolved clinical exome cases

Patient ID	Rank	Gene	Zygosity	OMIM API?	Phenotypic Series	Phenolyzer score	ACMG criteria	ACMG	ClinVar	Reported MoI	Type of variant	Variant^a	rs ID	N HPO terms	N Dis Terms	N genes with rare variant	CallQ	Depth	Ref	Alt	Lof	N Het	N Hom
Illumina
SNG190	1	PTCH1	Het	0	0	1.000	pvs1,ps1,pm1,pm2	P	P	AD	stop-gain	p.Arg267Ter	rs863224650	8	0	145	99	62	37	25	1	1	0
SNG217	1	EHMT1	Het	0	0	0.764	pvs1,ps1,pm1,pm2	P	P	AD	stop-gain	p.Arg1168Ter	rs121918301	27	0	218	99	130	71	59	2	1	0
SNG178	2	ARID1A	Het	0	0	0.127	pvs1,pm1,pm2	P	None	AD	frameshift	p.Val1024AlafsTer10	None	14	0	207	99	143	120	12	1	1	0
SNG129	5	NFIX	Het	0	0	0.038	pvs1,pm1,pm2	P	None	AD	stop-gain	p.Gln232Ter	None	25	4	100	99	70	35	35	1	1	0
SNG133	7	GLI2	Het	0	0	0.003	pvs1,pm2	LP	None	AD	frameshift	p.Ala641ProfsTer59	None	9	1	138	78	4	2	2	1	1	0
SNG057	3	ANKRD11	Het	0	0	0.026	pm2	Undefined	None	AD	stop-gain	p.Ser1884Ter	None	16	1	108	99	49	23	26	1	1	0
SNG152	4	GAS1	Het	0	0	0.002	pm2,pp3	Undefined	None	AD	missense	p.Arg45Gly	rs922820794	4	0	118	31	6	2	4	0	1	0
SNG212	1	LRP5	Het	0	0	0.161	pm2,pp3	Undefined	None	AD	missense	p.Thr297Ile	rs765013945	11	0	233	99	96	36	60	0	1	0
SNG197	4	BMP2	Het	0	0	0.058	pm1,pp3	Undefined	None	AD	missense	p.Arg131Ser	rs140417301	13	0	109	99	47	26	21	0	1	0
SNG058	1	EHMT1	Het	1	0	0.044	pm2	Undefined	None	AD	splice-donor	c.3716+1G>T	None	15	1	99	99	34	17	17	2	1	0
SNG086	1	SHANK3	Het	0	0	0.261	pp3	Undefined	VUS	AD	missense	p.Pro1665Thr	rs749130556	15	0	111	99	35	14	21	0	1	0
Mean				0.09	0.00	0.23								14.27	0.64	144.18	90.91	61.45	34.82	25.64
SD				0.30	0.00	0.34								6.83	1.21	50.65	20.84	45.62	34.20	19.27
Ion Torrent
SNG113	1	KMT2D	Het	1	1	0.000	pvs1,pm2	LP	None	AD	missense	p.Gly965Arg	None	13	1	830	20	15	5	10	22	1	0
SNG107	4	FRMPD4	Hom	1	1	0	pm2	Undefined	None	XLR	missense	p.Gly691Val	rs200183778	11	1	845	200	45	45	0	0	0	1
SNG025	1	RAI1	Het	0	0	0.392	pm2	Undefined	None	AD,IC	frameshift	p.Asn1254LysfsTer61	None	17	0	805	28	91	69	22	7	1	0
SNG078	1	TCF4	Het	0	0	0.366	pm2,pp3	Undefined	None	AD	missense	p.Ser78Cys	rs780638244	12	0	398	99	86	35	51	2	1	0
SNG084	1	RAI1	Het	1	1	0.796	pm2	Undefined	None	AD	missense	p.Gln306Ter	rs61753380	17	1	805	99	128	64	64	7	1	0
SNG060	1 2	EPG5	Het Het	1	0	1	pm2 pm2,pp3	Undefined Undefined	None None	AR	splice variant missense	c.6049+5G>A p.Ile1185Leu	None None	17	1	525	99 99	174 124	92 59	82 59	0	1 1	0 0
SNG112	1	BRAF	Het	0	0	0.773	pm2	Undefined	None	AD	frameshift	p.Gly30AlafsTer24	None	16	0	412	15	23	9	14	2	1	0
Mean				0.57	0.43	0.48								14.71	0.57	660.00	76.83	64.67	37.83	26.83
SD				0.53	0.53	0.40								2.63	0.53	205.57	71.54	44.16	26.93	25.13

Three (SNG190, SNG178, SNG057) have been validated by Sanger sequencing of patient plus parents. Of these 18 variants, 6 classified as ACMG pathogenic or likely pathogenic, the remainder are undefined. Full details of these variants are provided in Table S2. Details of a further 27 putative candidate diagnoses that remain under clinical review are provided in Table S2. Rank indicates rank in our pipeline; OMIM API? indicates whether the diagnosis was made by direct access to the OMIM API (1 = yes; 0 = No); Phenotypic Series indicates whether the diagnosed gene was identified via the phenotypic series in OMIM (1 = yes; 0 = No). N Het is the number of individuals in the cohort heterozygous for the variant; N Hom the number of homozygous individuals. One patient was listed as a possible compound heterozygote.
AD autosomal dominant, AR autosomal recessive, IC isolated cases, P pathogenic, LP likely pathogenic, VUS variant of unknown significance (categorized as undefined in our pipeline), LoF number of loss-of-function variants seen in this gene in the cohort.
^aFull details of transcripts are provided in Table S2.

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Table 4 Details of pipeline performance for 18 candidate molecular diagnoses for previously unsolved cases based on Illumina TruSight or Ion Torrent sequencing as indicated. These 18 candidate variants were considered of immediate clinical relevance upon clinical review.

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