Table 1 Likely causative variants identified by exome sequencing in genes reported to be associated with hearing loss.

From: Genomic analysis of childhood hearing loss in the Yoruba population of Nigeria

Family	Individual with HL	Gene	Form of HL	Inheritance	Zygosity	HGVS transcript:nucleotide change	Predicted protein change	Splicing modification:MaxEntScan diff	SIFT function	PolyPhen-2 function prediction	MutationTaster	FATHMM-MKL or XF	MutationAssessor	Conservation based on phyloP	REVEL score	CADD score	MAF in YRI samples from the Coriell (Sanger sequencing)	MAF in YRI population (1000 genomes)	MAF in gnomAD in African/ African American population in percent	MAF in gnomAD (all populations) in percent	ACMG/AMP classification with HL specifications*
Variants identified in genes associated with nonsyndromic forms of hearing loss
2	II.3, II.4	*CIB2*	DFNB48	AR	Hom	NM_006383.4:c.556C>T	p.(Arg186Trp)	–	D	PbD	DC	B	M		0.418	34		0/216	0.052	0.005	Likely pathogenic
57	I.2	*ILDR1*	DFNB42	AR	Het	NM_001199799.2:c.775C>T	p.(Arg259Ter)	–			DC	B		C	–	42	0/236	ND	0	0.005	Pathogenic
57	I.2	*ILDR1*	DFNB42	AR	Het	NM_001199799.2:c.9G>A	p.(Trp3Ter)	–			DC	B			–	25.9	0/236	ND	ND	ND	Pathogenic
6	II.2	*MYO15A*	DFNB3	AR	Het	NM_016239.4:c.4888C>T	p.(Arg1630Cys)	–	D	PbD	DC	P	H		0.62	28.6		4/216	0.856	0.091	VUS
6	II.2	*MYO15A*	DFNB3	AR	Het	NM_016239.4:c.5777G>A	p.(Arg1926His)	–	D	PbD	DC	P	M	C	0.783	33		0/216	0.021	0.006	VUS
13	II.6	*MYO15A*	DFNB3	AR	Het	NM_016239.4:c.3196G>C	p.(Ala1066Pro)	–	D	B	Po	B	L		0.196	15.6		1/216	0.273	0.071	VUS
13	II.6	*MYO15A*	DFNB3	AR	Het	NM_016239.4:c.7006C>T	p.(Gln2336Ter)	–			DC	B			–	35	0/236	ND	ND	ND	Likely pathogenic
44	II.3	*MYO15A*	DFNB3	AR	Het	NM_016239.4:c.4216G>A	p.(Glu1406Lys)	–	D	PbD	DC	P	H	C	0.95	32	0/234	ND	0	0.001	VUS
44	II.3	*MYO15A*	DFNB3	AR	Het	NM_016239.4:c.6302T>C	p.(Leu2101Pro)	–	D	PbD	DC	P	M	C	0.836	32	0/236	ND	0.042	0.004	VUS
40	II.1	*TMPRSS3*	DFNB8/B10	AR	Hom	NM_024022.3:c.1363T>C	p.(Ter455ArgextTer9)	–			Po	P			–	<10		3/216	0.256	0.025	VUS
40	II.1	*TMPRSS3*	DFNB8/B10	AR	Hom	NM_024022.3:c.323-6G>A		4.423			DC	P			–	<10		0/216	0	0.0001	Pathogenic
23	II.1	*COL11A1*	DFNA37, Marshall syndrome, Stickler syndrome type II	AD	Het	NM_001854.4:c.1031C>T	p.(Thr344Met)	–	T	PbD		P	M	C	0.493	24.3		0/216	0.006	0.002	VUS
32	II.1	*COL11A1*	DFNA37, Marshall syndrome, Stickler syndrome type II	AD	Het	NM_001854.4:c.1314G>A	p.(Met438Ile)	–	T	PsD	DC	P	N	C	0.503	23.4	0/236	ND	ND	ND	VUS
32	II.1	*COL11A1*	DFNA37, Marshall syndrome, Stickler syndrome type II	AD	Het in trans - present in I.2 without HL	NM_001854.4:c.4049C>G	p.(Ser1350Cys)	–	T	PbD	DC	P	M	C	0.733	35	0/236	ND	ND	ND	VUS
51	II.4	*WFS1*	DFNA6/A14/A38, Wolfram-like syndrome (AD)	AD	Het	NM_006005.3:c.2029G>A	p.(Ala677Thr)	–	D	PsD	DC	P	M	C	0.73	23.5	0/236	ND	0	0.009	VUS
Variants identified in genes associated with nonsyndromic forms of hearing loss or Usher syndrome
8	II.4, II.5	*CDH23*	DFNB12, USH1D	AR	Compound Het	NM_022124.6:c.3176A>T	p.(Asp1059Val)	–		PbD	DC	P	H	C	0.965	34	0/236	ND	ND	ND	Likely pathogenic
8	II.4, II.5	*CDH23*	DFNB12, USH1D	AR	Compound Het	NM_022124.6:c.7872+1G>A		8.182			DC	Ph		C	–	32	0/236	ND	ND	ND	Pathogenic
21	II.2	*CDH23*	DFNB12, USH1D	AR	Het	NM_022124.6:c.271C>T	p.(Gln91Ter)	–			DC	B		C	–	40	0/236	ND	ND	ND	Pathogenic
		*CDH23*		AR	Het in cis with c.8177C>T	NM_022124.6:c.5237G>A	p.(Arg1746Gln)	–	T	B	DC	P	N	C	0.354	23.5	0/236	ND	0.008	0.007	Pathogenic
		*CDH23*		AR	Het in cis with c.5237G>A	NM_022124.6:c.8177C>T	p.(Pro2726Leu)	0.683	D	PsD	DC	P	N	C	0.268	27.6	0/236	ND	0	0.001	Likely pathogenic
60	I.2	*CDH23*	DFNB12, USH1D	AR	Compound Het	NM_022124.6:c.5505G>A	p.(Met1835Ile)	0.46	T	B	DC	P	N		0.1	22.4		0/216	0.169	0.05	VUS
		*CDH23*	DFNB12, USH1D	AR	Compound Het	NM_022124.6:c.9726del	p.(Ser3243ProfsTer5)	–			DC			C	–	36	2/236	ND	0.102	0.009	VUS
		*OTOF*	DFNB9	AR	Compound Het	NM_194248.3:c.245G>A	p.(Arg82His)	–	T	PsD	DC	P	L	C	0.23	23.9		1/216	0.6245	0.068	VUS
		*OTOF*	DFNB9	AR	Compound Het	NM_194248.3:c.3917A>C	p.(Lys1306Thr)	–	T	B	DC	P	L	C	0.454	23.4		0/216	0.279	0.021	VUS
56	I.1	*CDH23*	DFNB12, USH1D	AR	Het	NM_022124.6:c.2560C>T	p.(Arg854Cys)	–		PbD	DC	P	L		0.189	31	0/236	ND	0.004	0.001	VUS
56	I.1	*CDH23*	DFNB12, USH1D	AR	Het	NM_022124.6:c.3074G>A	p.(Gly1025Asp)	–		PsD	DC	P	M	C	0.925	33		0/216	1.177	0.35	VUS
56	I.2	*MYO7A*	DFNB2, USH1B	AR	Het unlikely to be in cis with the other variants	NM_000260.4:c.133-3C>A		4.21			DC	Ph		C	–	21.4	0/236	ND	ND	ND	VUS
		*MYO7A*		AR	Het	NM_000260.4:c.6355C>A	p.(Gln2119Lys)	−0.92	T	PbD	DC	P	M	C	0.767	34	0/236	ND	ND	ND	VUS
		*MYO7A*		AR	Het	NM_000260.4:c.5522C>T	p.(Thr1841Met)	–	D	PbD	DC	P	M	C	0.815	24.9	0/236	ND	0.01	0.006	VUS
5	III.2, III.3, III.4	*PCDH15*	DFNB23, USH1F	AR	Compound Het	NM_033056.4:c.3668_3669delTT	p.(Ile1223SerfsTer3)	–							–		0/236	ND	ND	ND	Pathogenic
5	III.2, III.3, III.4	*PCDH15*	DFNB23, USH1F	AR	Compound Het	NM_033056.4:c.1737C>G	p.(Tyr579Ter)	–			DC	B			–	26	0/236	ND	0	0	Pathogenic
29	II.3	*USH2A*	USH2A	AR	Compound Het	NM_206933.3:c.13361T>A	p.(Val4454Asp)	–	D	PbD	DC	P	M	C	0.371	28.3		2/216	0.224	0.02	VUS
29	II.3	*USH2A*	USH2A	AR	Compound Het	NM_206933.3:c.5612G>A	p.(Gly1871Asp)	–	D	PbD	DC	P	M	C	0.663	25.2		0/216	0.371	0.105	VUS
Variants found in genes associated with other syndromic forms of hearing loss
14	II.1	*CHD7*	CHARGE syndrome, Hypogonadotropic hypogonadism 5 with or without anosmia	AD variable penetrance and expressivity	Het	NM_017780.4:c.8276A>G	p.(Gln2759Arg)	–	D	PsD	DC	P	M	C	0.236	26.9	0/236	ND	ND	ND	VUS
16	II.1	*CHD7*	CHARGE syndrome, Hypogonadotropic hypogonadism 5 with or without anosmia	AD variable penetrance and expressivity	Het	NM_017780.4:c.2613+5G>A		3.527			DC	Ph		C	–	14.35		0/216	0.027	0.007	VUS
10	II.2, II.3	*OPA1*	Optic atrophy plus syndrome	AD variable penetrance and expressivity	Het	NM_015560.2:c.2794C>T	p.(Arg932Cys)	–	D	PbD	DC	P	M		0.855	28.6	0/236	ND	0.008	0.002	VUS
26	II.4	*SPTLC1*	Neuropathy, hereditary sensory and autonomic type IA	AD variable penetrance	Het	NM_001368273.1:c.881C>T	p.(Thr294Met)	–	D	PbD	DC	P	L	C	0.775	33	0/236	ND	0	0	VUS

* Variants were classified according to the ACMG/AMP Guidelines for interpretation of sequence variants in HL genes [22] with two modifications. The genetic causes of HL have not yet been well characterized in the Yoruba (YRI) population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their “high” MAF. PP3 criterion was applied even if the REVEL score was below 0.7, if at least two of the algorithms used predicted that the variant was damaging or likely damaging (Fig. 1). Further information regarding these variants is presented in Supplementary Table 4.
ND no record in the database, AD autosomal dominant, AR autosomal recessive, Het heterozygous, Hom homozygous, B benign, C conserved, D damaging, DC disease causing, H high, L low, M medium, N neutral, P pathogenic, PbD probably damaging, Ph pathogenic (high confidence), PsD possibly damaging, Po polymorphism, T tolerated.

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Table 1 Likely causative variants identified by exome sequencing in genes reported to be associated with hearing loss.

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