Addition of an affected family member to a previously ascertained autosomal recessive nonsyndromic hearing loss pedigree and systematic phenotype-genotype analysis of splice-site variants in MYO15A

Yang, Jin-Yuan; Wang, Wei-Qian; Han, Ming-Yu; Huang, Sha-Sha; Wang, Guo-Jian; Su, Yu; Xu, Jin-Cao; Fu, Ying; Kang, Dong-Yang; Yang, Kun; Zhang, Xin; Liu, Xing; Gao, Xue; Yuan, Yong-Yi; Dai, Pu

doi:10.1186/s12920-022-01368-9

Table 1 Summary of splice-site variants in MYO15A registered in HGMD

From: Addition of an affected family member to a previously ascertained autosomal recessive nonsyndromic hearing loss pedigree and systematic phenotype-genotype analysis of splice-site variants in MYO15A

	Allele1					Allele2
	Location	Nucleotide change	ACMG classification (codes)	MAF (gnomAD)	Zygosity	Location	Nucleotide change	AA change
1	Chr17:18,026,708	c.3609+985G > A	LP PS4+(PM2+PM3+PP1+PP3)	0	Hom
					Het	Chr17:18,052,889	c.7207G > T	p.Asp2403Tyr
					Het	Chr17:18,065,953	c.9572G > A	p.Arg3191His
2	Chr17:18,028,546	c.3756+1G > A	P (PVS1+PP5+PM2+PP3)	0.00000802	Het	Chr17:18,039,881	c.4660G > A	p.Ala1554Thr
3	Chr17:18,028,546	c.3756+1G > T	P (PVS1+PM2+PP3+PP5)	0.0000318	Hom
4	Chr17:18,028,546	c.3756++1G > C	P (PVS1+PM2+PP5+PP3)	0	Het	Chr17:18,052,097	c.6787G > A	p.Gly2263Ser
5	Chr17:18,029,626–18,029,658	c.3757-32_3757-1del32	P (PVS1+PM2+PP3)	0.00000808	NA
6	Chr17:18,029,659	c.3757-2A > G	P (PVS1+PM2+PP3)	0	Hom
7	Chr17:18,029,771	c.3866+1G > A	P (PVS1+PM2+PP5+PP3)	0.0000161	Hom
7	Chr17:18,029,771	c.3866+1G > A	P (PVS1+PM2+PP5+PP3)	0.0000161	NA
8	Chr17:18,030,103	c.3867-2A > C	P (PVS1+PM2++PP3)	0	NA
9	Chr17:18,030,104	c.3867-1G > A	P (PVS1+PM2+PP3)	0	Het	Chr17:18,045,553	c.5810G > A	p.Arg1937His
10	Chr17:18,034,657	c.4142+1G > T	P (PVS1+PM2+PP3)	0	Hom
11	Chr17:18,034,661	c.4142+5G > A	VUS (PM2+PP3)	0	Hom
12	Chr17:18,035,881	c.4320+1G > A	P (PVS1+PM2+PP5+PP3)	0	Het	Chr17:18,049,349	c.6437G > A	p.Arg2146Gln
13	Chr17:18,039,139	c.4596+1G > A	P (PVS1+PM2+PP5+PP3	0.0000122	Hom
13	Chr17:18,039,139	c.4596+1G > A	P (PVS1+PM2+PP5+PP3	0.0000122	Het	Chr17:18,035,812	c.4252G > A	p.Gly1418Arg
14	Chr17:18,039,140	c.4596+2dupT	VUS (PM2+PP3)		Het	Chr17:18,045,553	c.5810G > A	p.Arg1937His
15	Chr17:18,039,729	c.4597-2A > G	P (PVS1+PM2+PP5+PP3)	0.00000803	Het	Chr17:18,057,199	c.8077del	p.Leu2693CysfsTer45
15	Chr17:18,039,729	c.4597-2A > G	P (PVS1+PM2+PP5+PP3)	0.00000803	Het	Chr17:18,077,164	c.10420A > G	p.Ser3474Gly
16	Chr17:18,039,790	c.4655+1G > A	P (PVS1+PM2+PP3)	0.0000201	NA	Chr17:18,051,884	c.6764+2 T > A	-
17	Chr17:18,040,994	c.4875+1G > T	P (PVS1+PM2+PP3)	0	Het	Chr17:18,030,390	c.3943G > A	p.Gly1315Arg
18	Chr17:18,041,561	c.5007+1G > C	P (PVS1+PM2+PP5+PP3)	0	Het	Chr17:18,047,111	c.6046+1G > A	-
19	Chr17:18,042,251	c.5133+1G > A	P (PVS1+PM2+PP5+PP3)	0	Het	Chr17:18,055,426	c.7894G > T	p.Val2632Leu
20	Chr17:18,042,838	c.5134-10C > G	VUS (PM2+BP4)	0	Het	Chr17:18,025,140	c.3026C > A	p.Pro1009His
21	Chr17:18,043,829	c.5212-2A > G	P (PVS1+PM2+PP5+PP3)	0	Het	Chr17:18,039,776	c.4642G > A	p.Ala1548Thr
22	Chr17:18,044,458	c.5531+1G > C	P (PVS1+PM2+PP5+PP3)	0	Het	Chr17:18,058,662	c.8375 T > C	p.Val2792Ala
23	Chr17:18,045,392	c.5650-1G > A	P (PVS1+PM2+PP3)	0.0000319	Hom
24	Chr17:18,046,155	c.5910+1G > T	P (PVS1+PM2+PP3)	0	NA
25	Chr17:18,046,936	c.5964+3G > A	LP (PM2+PM3+PP1+PP3+PP5)	0.0000287	Het	Chr17:18,058,662	c.8375 T > C	p.Val2792Ala
					Het	Chr17:18,060,348	c.8681_8682insA	p.His2895ThrfsTer31
					Het	Chr17:18,061,038	c.8791del	p.Trp2931GlyfsTer103
					NA
26	Chr17:18,047,021	c.5965-8C > T	VUS (PM2+BP4)	0.00011	Het	Chr17:18,024,711	c.2597C > G	p.Ser866Trp
26	Chr17:18,047,021	c.5965-8C > T	VUS (PM2+BP4)	0.00011	Het	Chr17:18,024,532	c.2418C > T	p.Phe806 =
27	Chr17:18,047,111	c.6046+1G > A	P (PVS1+PM2+PP5+PP3)	0.0000261	Het	Chr17:18,041,561	c.5007+1G > C
27	Chr17:18,047,111	c.6046+1G > A	P (PVS1+PM2+PP5+PP3)	0.0000261	Het
28	Chr17:18,047,315	c.6177+1G > T	P (PVS1+PM2+PP3+PP5)	0	Het	Chr17:18,023,242	c.1128C > A	p.Tyr376Ter
					Het	Chr17:18,039,887	c.4666G > A	p.Ala1556Thr
					Het	Chr17:18,027,845	c.3658_3662del	p.Glu1221TrpfsTer23
					NA
29	Chr17:18,047,809	c.6178-2A > G	P (PVS1+PP5+PM2+PP3)	0	Hom
30	Chr17:18,047,810	c.6178-1G > A	P (PVS1+PM2+PP3+PP5)	0	Het	Chr17:18,022,844	c.730G > A	p.Asp244Asn
31	Chr17:18,047,907	c.6273+1G > A	P (PVS1+PM2+PP5+PP3)	0	Hom
32	Chr17:18,051,884	c.6764+2 T > A	P (PVS1+PM2+PP3)	0.0000194	Het	Chr17:18,039,790	c.4655+1G > A
					Het	Chr17:18,036,569	c.4351G > A	p.Asp1451Asn
					Het	Chr17:18,029,748	c.3844C > T	p.Arg1282Trp
					Het	Chr17:18,043,906	c.5287C > T	p.Arg1763Trp
33	Chr17:18,052,267	c.6956+1G > A	P (PVS1+PM2+PP3+PP5)	0.00000491	Het
34	Chr17:18,052,275	c.6956+9C > G	VUS (PM2+PP3)	0.00000535	Het	Chr17:18,075,505	c.10251_10253del	p.Phe3420del
34	Chr17:18,052,275	c.6956+9C > G	VUS (PM2+PP3)	0.00000535	Het	Chr17:18,049,252	c.6340G > A	p.Val2114Met
35	Chr17:18,054,080	c.7395+1G > A	P (PVS1+PM2+PP3)	0	NA
36	Chr17:18,054,082	c.7395+3G > C	VUS (PM2+PP3)	0	Hom
37	Chr17:18,054,082	c.7395+3G > A	VUS (PM2+PP3)	0.00000504	Hom
38	Chr17:18,054,149	c.7396-1G > A	P (PVS1+PP5+PM2+PP3)	0.0000141	Het	Chr17:18,059,601	c.8552C > T	p.Ala2851Val
					Het	Chr17:18,058,523	c.8324G > A	p.Arg2775His
					Het	Chr17:18,040,941	c.4823C > A	p.Ala1608Glu
					Het	Chr17:18,045,435	c.5692C > T	p.Arg1898Ter
39	Chr17:18,054,845	c.7787+4A > G	VUS (PM2+PP3)	0	Hom
40	Chr17:18,055,266	c.7893+1G > A	P (PVS1+PM2+PP3+PP5)	0.0000124	Het	Chr17:18,052,097	c.6787G > A	p.Gly2263Ser
40	Chr17:18,055,266	c.7893+1G > A	P (PVS1+PM2+PP3+PP5)	0.0000124	Het	Chr17:18,051,413	c.6580C > T	p.Arg2194Trp
41	Chr17:18,055,500	c.7966+2 T > C	P (PVS1+PP5+PM2+PP3)	0	Het	Chr17:18,034,837	c.4198G > A	p.Val1400Met
42	Chr17:18,057,211	c.8088+1G > A	P (PVS1+PM2+PP3+PP5)	0.00000402	NA
43	Chr17:18,057,993	c.8149-1G > A	P (PVS1+PM2+PP5+PP3)	0	Hom
44	Chr17:18,058,072	c.8224+3A > G	VUS (PM2+PP3)	0	Hom
45	Chr17:18,059,652	c.8601+2 T > G	P (PVS1+PM2+PP5+PP3)	0	NA
45	Chr17:18,059,652	c.8601+2 T > G	P (PVS1+PM2+PP5+PP3)	0	NA
46	Chr17:18,060,267	c.8602-1G > C	P (PVS1+PM2+PP3)	0	Het
47	Chr17:18,060,549	c.8788+5G > T	VUS (PM2+PP3)	0	Hom
48	Chr17:18,061,836	c.8968-1G > C	P (PVS1+PM2+PP3+PP5)	0	Hom
49	Chr17:18,061,836	c.8968-1G > T	P (PVS1+PM2+PP5+PP3)	0.00000803	Het	Chr17:18,057,172	c.8050 T > C	p.Tyr2684His
49	Chr17:18,061,836	c.8968-1G > T	P (PVS1+PM2+PP5+PP3)	0.00000803	Hom
50	Chr17:18,061,958	c.9083+6 T > A	LP (PS3+PM2+PP1+PP5+BP4)	0	Hom
51	Chr17:18,062,238	c.9084-1G > T	P (PVS1+PM2+PP3+PP5)	0	NA
52	Chr17:18,062,662	c.9229+1G > A	P (PVS1+PM2+PP3)	0	Hom
53	Chr17:18,062,663	c.9229+2 T > C	P (PVS1+PM2+PP3+PP5)	0	Hom
54	Chr17:18,064,763	c.9517+2 T > C	P (PVS1+PM2+PP5+PP3)	0.00000402	Het	Chr17:18,066,565	c.9620G > A	p.Arg3207His
55	Chr17:18,065,897	c.9518 − 2A > G	P (PVS1+PM2+PP3)	0.00000809	Hom
56	Chr17:18,066,636	c.9690+1G > A	P (PVS1+PP5+PM2+PP3)	0	Hom
56	Chr17:18,066,636	c.9690+1G > A	P (PVS1+PP5+PM2+PP3)	0	Hom
57	Chr17:18,077,237	c.10491+2 T > C	P (PVS1+PM2+PP3+PP5)	0	Het	Chr17:18,023,248	c.1137del	p.Tyr380MetfsTer64
58	Chr17:18,082,081	c.10492-2dupA	P (PVS1+PM2+PP3)	0	Het	Chr17:18,057,446	c.8090 T > C	p.Val2697Ala

	Allele2		Hearing loss phenotype	Onset	Ethnicity	References
	ACMG classification (codes)	MAF (GnomAD)	Hearing loss phenotype	Onset	Ethnicity	References
1			Severe to profound/moderate	Prelingual	Palestinian	Rayyan et al. [8]
	VUS (PM2+PP3+PP5)	0	Moderate	Prelingual	Palestinian	Rayyan et al. [8]
	LP (PM2+PM5+PP3+PP5)	0.0000401	Moderate to severe	Prelingual	Palestinian	Rayyan et al. [8]
2	VUS (PM2+PP3	0.0000722	Profound, Progressive	5yo	Japanese	Sakuma et al. [9]
3			Profound	Congenital	Pakistani	Liburd et al. [10]
4	LP (PM2+PM5+PP3)	0.0000309	Severe to profound, symm	Congenital	NA	Sloan-Heggen et al. [11]
5			NA	NA	Chinese(Taiwanese)	Wu et al. [12]
6			NA	Prelingual or congenital	Peruvian	Figueroa-Ildefonso et al. [13]
7			Severe to profound	Prelingual	Palestinian	Rayyan et al. [8]
7			Severe to profound	NA	Pakistani	Nal et al. [14]
8			NA	NA	European(major)	Hou et al. [15]
9	VUS (PM2+PP3)	0.0000282	NA	NA	Iranian	Bazazzadegan et al. [16]
10			Severe to profound	Prelingual	Iranian	Sloan-Heggen et al. [17]
11			Severe to profound	Prelingual	Palestinian	Rayyan et al. [8]
12	LP (PM1+PM2+PP3+PP5)	0.0000121	Severe to profound	Diagnosed at an early age	Korean	Woo et al. [18]
13			NA	< 5yo	Iranian	Motavaf et al. [19]
13	LP (PM2+PP5+PP3)	0.00000803	Profound	Congenital	Chinese	Zhang et al. [20]
14	VUS (PM2+PP3	0.0000282	Severe to profound, asymmetric	Childhood	NA	Sloan-Heggen et al. [11]
15	LP (PVS1++PM2)	0	Profound	Congenital	Chinese	Zhang et al. [20]
15	LB (BP6+BP4+MP2)	0.000508
16	P (PVS1+PM2+PP3)	0.0000194	NA	Congenital	NA	Sloan-Heggen et al. [17]
17	P (PVS1+PM2+PM5+PP3)	0	Profound	Congenital	Chinese	Liang et al. [21]
18	P (PVS1+PM2+PP5+PP3)	0.0000261	NA	Prelingual	European	Sommen et al. [22]
19	LP (PVS1+PM2)	0.00000647	NA	Congenital or prelingual	Turkish	Bademci et al. [23]
20	B (BS1+BS2+BP4)	0.00591	NA	NA	Chinese	Sun et al. [24]
21	VUS (PM2+PP3	0.0000201	Severe to profound	Congenital or prelingual	Turkish	Atik et al. [25]
22	VUS (PM2+PP3+PP5	0.00000401	Profound, symmetric	Congenital	Chinese	This study
23			NA	NA	Turkish	Duman et al. [26]
24			Severe to profound	Prelingual	Iranian	Sloan-Heggen et al. [17]
25	VUS (PM2+PP3+PP5	0.00000401	Severe to profound, symmetric	Prelingual	Chinese	Gao et al. [7]
	P (PVS1+PM2+PP3)	0	NA	NA	Chinese	Sun et al. [24]
	P (PVS1+PM2+PP3)	0	Profound	Congenital	Chinese	Zhang et al. [20]
			NA	NA	Chinese	Yang et al. [27]
26	VUS (PM2	0	Profound	Prelingual	Czech	Safka Brozkova et al. [28]
26	LB (BP4+BP7+PM2)	0.000996
27	P (PVS1+PM2+PP5+PP3)	0	NA	Prelingual	European	Sommen et al. [22]
27			NA	Prelingual	European	Schrauwen et al. [29]
28	P (PVS1+PM2+PP3)	0	Severe to profound, symmetric	NA	Chinese	Sun et al. [30]
	VUS (PM2+PP3)	0.0000201	Severe, progressive	Prelingual(5yo)	Chinese	Zhang et al. [20]
	P (PVS1+PM2+PP3)	0.00000807	Profound, symmetric	Congenital	Chinese	Wang et al. [31]
			NA	NA	Chinese	Yuan et al. [32]
29			NA	NA	Pakistani	Rehman et al. [33]
30	VUS (PM2)	0.000392	NA	NA	Czech	Safka Brozkova et al. [28]
31			NA	Congenital or prelingual	Iranian	Yan et al. [34]
32	P (PVS1+PM2+PP3)	0.0000201	NA	Congenital	NA	Sloan-Heggen et al. [17]
	P (PM2+PP5+PP3)	0.000012	Profound	NA	Australian	Downie et al. [35]
	VUS (PM2)	0.0000563	NA	NA	Dutch	Zazo Seco et al. [36]
	VUS (PM2+PP3)	0.00177
33			NA	NA	Chinese(Taiwanese)	Wu et al. [12]
34	VUS (PM2+PP3)	0.000016	NA	NA	Chinese	Yang et al. [27]
34	LP (PM1+PM2+PP3+PP5)	0.00000402	NA	NA	Chinese	Yang et al. [27]
35			Severe to profound	Prelingual	Iranian	Sloan-Heggen et al. [17]
36			Severe to profound	NA	Tunisian	Belguith et al. [37]
37			Severe to profound	NA	Tunisian	Riahi et al. [38]
38	VUS (PM2+PP5+PP3)	0.000012	Severe to profound	NA	Vietnamese	Han et al. [39]
	VUS (PM2+PP3)	0.00000804	Severe to profound	NA	Vietnamese	Han et al. [39]
	VUS (PM2+PP3)	0	Profound	Congenital	Chinese	Zhang et al. [20]
	P (PVS1+PM2+PP5+PP3)	0.00000401	Severe	Congenital	Chinese	Zhang et al. [20]
39			NA	NA	Chinese	Yang et al. [27]
40	LP (PM2+PM5+PP3)	0.0000309	NA	NA	Dutch	Zazo Seco et al. [36]
40	VUS (PM1+PM2)	0.000141	NA	Prelingual	European	Sommen et al. [22]
41	P (PP5+PM2+PP3)	0.0000361	NA	Congenital	NA	Sloan-Heggen et al. [11]
42			NA	NA	Chinese	Yuan et al. [32]
43			Profound	NA	N-African	Boudewyns et al. [40]
44			NA	NA	Pakistani	Rehman et al. [33]
45			Profound	Prelingual	Iranian	Sloan-Heggen et al. [17]
45			Severe to profound	NA	Egyptian	Budde et al. [41]
46			NA	NA	Chinese(Taiwanese)	Wu et al. [12]
47			Severe to profound	Prelingual	Palestinian	Rayyan et al. [8]
48			Profound	Prelingual	Turkish	Kalay et al. [42]
49	VUS (PM2+PP5+PP3)	0.0000602	Severe to profound	Congenital	Spanish	Cabanillas et al. [43]
49			Severe, stable, symmetric	Prelingual	NA	García-García et al. [44]
50			Profound	Congenital	Arab	Danial-Farran et al. [45]
51			NA	NA	Chinese	Yuan et al. [32]
52			Severe to profound	NA	Tunisian	Belguith et al. [37]
53			NA	NA	Pakistani	Rehman et al. [33]
54	VUS (PM2+PM5+PP3)	0.0000441	NA	Congenital	NA	Sloan-Heggen et al. [11]
55			Severe to profound	Congenital	Pakistani	Khan et al. [46]
56			Profound	Prelingual	Chinese(Uyghur)	Chen et al. [47]
56			Profound, symmetric	Congenital	Chinese	Zhang et al. [48]
57	P (PVS1+PP5+PM2)	0.0000962	Severe	NA	Australian	Downie et al. [35]
58	P (PVS1+PM2+PP5+PP3)	0.000257	NA	Congenital or prelingual	Turkish	Yan et al. [34]

N/A Not available; Het Heterozygous; Hom Homozygous; P Pathogenic; LP Likely pathogenic; VUS Variants with uncertain significance; B Benign; LB Likely benign

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