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)
From: A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project
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 |