Critical assessment of variant prioritization methods for rare disease diagnosis within the rare genomes project

Stenton, Sarah L.; O’Leary, Melanie C.; Lemire, Gabrielle; VanNoy, Grace E.; DiTroia, Stephanie; Ganesh, Vijay S.; Groopman, Emily; O’Heir, Emily; Mangilog, Brian; Osei-Owusu, Ikeoluwa; Pais, Lynn S.; Serrano, Jillian; Singer-Berk, Moriel; Weisburd, Ben; Wilson, Michael W.; Austin-Tse, Christina; Abdelhakim, Marwa; Althagafi, Azza; Babbi, Giulia; Bellazzi, Riccardo; Bovo, Samuele; Carta, Maria Giulia; Casadio, Rita; Coenen, Pieter-Jan; De Paoli, Federica; Floris, Matteo; Gajapathy, Manavalan; Hoehndorf, Robert; Jacobsen, Julius O. B.; Joseph, Thomas; Kamandula, Akash; Katsonis, Panagiotis; Kint, Cyrielle; Lichtarge, Olivier; Limongelli, Ivan; Lu, Yulan; Magni, Paolo; Mamidi, Tarun Karthik Kumar; Martelli, Pier Luigi; Mulargia, Marta; Nicora, Giovanna; Nykamp, Keith; Pejaver, Vikas; Peng, Yisu; Pham, Thi Hong Cam; Podda, Maurizio S.; Rao, Aditya; Rizzo, Ettore; Saipradeep, Vangala G.; Savojardo, Castrense; Schols, Peter; Shen, Yang; Sivadasan, Naveen; Smedley, Damian; Soru, Dorian; Srinivasan, Rajgopal; Sun, Yuanfei; Sunderam, Uma; Tan, Wuwei; Tiwari, Naina; Wang, Xiao; Wang, Yaqiong; Williams, Amanda; Worthey, Elizabeth A.; Yin, Rujie; You, Yuning; Zeiberg, Daniel; Zucca, Susanna; Bakolitsa, Constantina; Brenner, Steven E.; Fullerton, Stephanie M.; Radivojac, Predrag; Rehm, Heidi L.; O’Donnell-Luria, Anne

doi:10.1186/s40246-024-00604-w

Human Genomics

Table 1 Detection of causal variants

From: Critical assessment of variant prioritization methods for rare disease diagnosis within the rare genomes project

Proband	Gene symbol	Sequencing provided	Inheritance	Known gene for phenotype	Variant call quality	Variant allele frequency (gnomAD v2 exomes, v3 genomes)	Variant functional consequence	Variant deleteriousness prediction	ACMG/AMP classification	seqr search returning the variant (total variants returned by search)	Number of models with the causal variant(s) at rank 1	Number of models with the causal variant(s) at rank 1–5	Number of models with the causal variant(s) at rank 1–10	Number of models with the causal variant(s) at rank 1–20	Number of models with the causal variant(s) at rank 1–50	Number of models with the causal variant(s) at rank 1–100
P28	FGFR2	Trio, unaffected parents	De novo	Yes	DP 27, GQ 99, AB 0.48	Absent	Missense	REVEL 0.98	P	De Novo/Dominant Restrictive (3)	36	46	46	47	47	47
P11	TPM2	Proband-only	Dominant	Yes	DP 48, GQ 99, AB 0.54	Absent	Missense	REVEL 0.89	VUS	De Novo/Dominant Restrictive (191)	17	40	41	44	47	47
P4	NALCN	Trio, unaffected parents	De novo	Yes	DP 34, GQ 99, AB 0.44	Absent	Missense	REVEL 0.94	LP	De Novo/Dominant Restrictive (3)	27	37	39	40	44	46
P7	EHMT1	Trio, unaffected parents	De novo	Yes	DP 50, GQ 99, AB 0.36	Absent	Frameshift	pLoF	LP	De Novo/Dominant Permissive (23)	27	34	36	37	38	40
P2	FAM111B	Proband-only	Dominant	Yes	DP 31, GQ 99, AB 0.55	Absent	Missense	REVEL 0.55	LP	De Novo/Dominant Restrictive (202)	15	27	33	35	41	41
P21	BICC1	Trio, unaffected parents	De novo	Yes	DP 31, GQ 99, AB 0.29	Absent	Missense	REVEL 0.19	LP	De Novo/Dominant Restrictive (2)	3	21	25	28	33	36
P24	KMT2D	Trio, unaffected parents	De novo	Yes	DP 49, GQ 99, AB 0.33	Absent	Missense	REVEL 0.36	LP	De Novo/Dominant Restrictive (3)	9	19	28	30	34	34
P22	GRIN2A	Duo, unaffected mother	Unknown	Yes	DP 25, GQ 99, AB 0.44	Absent	Nonsense	pLoF	P	De Novo/Dominant Restrictive (96)	6	19	23	32	34	34
P23	GNAI1	Trio, unaffected parents	De novo	Yes	DP 42, GQ 99, AB 0.45	Absent	Missense	REVEL 0.82	LP	De Novo/Dominant Restrictive (3)	14	19	19	21	29	31
P16	DLG4	Trio, unaffected parents	De novo	Yes	DP 27, GQ 99, AB 0.44	Absent	Frameshift	pLoF	LP	De Novo/Dominant Restrictive (4)	10	18	22	24	25	26
P27	TUBB8	Quad, affected sibling	Dominant	Yes	DP 26, GQ 99, AB 0.46	Absent	Missense	REVEL 0.31	VUS	Custom Panel Restrictive (4)*	11	18	20	22	23	23
P19	CLTC	Trio, unaffected parents	De novo	Yes	DP 39, GQ 99, AB 0.41	Absent	Splice acceptor	pLoF	LP	De Novo/Dominant Restrictive (4)	8	13	16	17	18	18
P5	PI4KA	Duo, unaffected father	Recessive	Phenotype expansion	DP 36, GQ 99, AB 0.56; DP 45, GQ 99, AB 0.56	0.00007230; Absent	Nonsense; Missense	pLoF; REVEL 0.73	P; LP	Recessive Restrictive (12)	6	9	12	12	15	18
P6	KCND2	Duo, unaffected father	Unknown	Yes	DP 37, GQ 99, AB 0.57	Absent	Missense	REVEL 0.84	LP	De Novo/Dominant Restrictive (107)	0	3	5	12	22	26

The 14 solved (true positive) cases are displayed with the causal gene, inheritance pattern, functional consequence of the causal variant(s), amount of familial sequencing provided in the challenge, and the ACMG/AMP classification of the variant(s). The number of models, out of 52, ranking the variant at position 1, 1–5, 1–10, 1–20, 1–50, and 1–100 are depicted. The probands are displayed in decreasing order by the number of causal variants submitted at rank position 1–5 by the models (emboldened), considered reasonable performance for a prediction metric. *Infertility gene panel search (93 genes) does not consider segregation. P, pathogenic; LP, likely pathogenic; VUS, variant of uncertain significance; pLoF, predicted loss-of-function (frameshift, nonsense, splice acceptor, and splice donor variants)

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