Table 1.

Diagnostic outcomes for seven individuals after clinical and functional characterisation of the splicing variant. Five individuals underwent RNA studies, of which four received a new diagnosis. In two additional individuals, a diagnosis was reached without the need for RNA studies. In total, a new diagnosis was confirmed for six individuals. Note that the given HPO terms are “abstracted” (see the “Methods” section) to protect confidentiality. *In participants 83 and 94, a new diagnosis was reached without the need for functional evaluation. **This exit questionnaire outcome was updated after the participant was identified by this study. DS_any: the probability that the variant has any impact on splicing (see the “Methods” section). DS_max: the maximum SpliceAI delta score of the variant. DS_max_type: the predicted splicing impact with the maximum delta score (DS_DL = donor loss, DS_DG = donor gain, DS_AL = acceptor loss, DS_AG = acceptor gain)

ID	Chrom	Pos	Ref	Alt	Region	Site	Symbol	ENST	DS_any	DS_max	DS_max type	Tier	Max tier	Exit questionnaire	HPO terms (abstracted)	Splicing impact	Outcome
74	chr1	26767787	C	G	acceptor	-3	ARID1A	ENST00000324856	0.71	0.65	DS_AL	3	3	No data	Aplasia/Hypoplasia of the mandible, Advanced eruption of teeth, Abnormal pulmonary valve morphology, Abnormality of calvarial morphology, Abnormality of cardiovascular system morphology, Oral cleft	Exon skipping	New diagnosis
261	chr10	74989117	G	A	donor	+5	KAT6B	ENST00000287239	0.98	0.98	DS_DL	3	3	Case not solved	Hypothyroidism	Exon skipping	New diagnosis
259	chr17	62596679	G	A	donor	+5	TLK2	ENST00000326270	0.97	0.96	DS_DL	3	3	Case not solved	Abnormality of globe location, Abnormal facial shape, Facial asymmetry, Abnormal heart sound, Cutaneous syndactyly, Abnormal ear morphology, Neurodevelopmental delay, Short stature, Abnormal digit morphology, Decreased body weight, Intrauterine growth retardation, Abnormality of higher mental function, Motor delay, Language impairment, Gait disturbance, Abnormal location of ears	Exon skipping	New diagnosis
249	chr16	8905182	C	A	donor	+5	USP7	ENST00000344836	0.932	0.8	DS_DL	3	3	Case not solved	Motor delay, Abnormal size of the palpebral fissure, Abnormal hair quantity, Abnormality of globe location, Facial hypertrichosis, Neurological speech impairment, Abnormality of higher mental function, Abnormal metatarsal morphology	Exon skipping	New diagnosis
94	chr6	79002126	T	G	acceptor	-2	PHIP	ENST00000275034	1	1	DS_AL	3	2	Case not solved	Abnormality of higher mental function, Motor delay, Neurodevelopmental delay, Macrotia, Language impairment, Finger clinodactyly, Abnormal muscle tone, Facial hypertrichosis	N/A	New diagnosis*
83	chr17	29491782	A	G	acceptor	-2	TAOK1	ENST00000261716	0.992	0.99	DS_AL	3	3	Case solved, same variant**	Renal agenesis, Hemangioma, Abnormality of joint mobility, Hypotonia, Increased head circumference, Neurodevelopmental delay	N/A	New diagnosis*
32	chr12	79808598	T	A	acceptor	-21	PPP1R12A	ENST00000450142	0	0	DS_AG	N/A	3	Case not solved	Increased head circumference, Abnormal thorax morphology, Bowing of the legs, Growth delay, Limb undergrowth, Abnormality of joint mobility, Short digit, Neurodevelopmental abnormality, Abnormality of movement	Normal splicing	Unsolved