Genome annotation for clinical genomic diagnostics: strengths and weaknesses

Table 1 Examples of disease-causing variation with associated HGVS nomenclature

Location	Gene	Variation	HGVS nomenclature	ACMG clinical significance	Associated disorder	Reference
5′ UTR	FMR1	Expansion	NM_002024.5(FMR1):c.-128_-126(200)	Pathogenic	Fragile X syndrome	[186]
CDS	GRIN2A	Nonsense	NM_000833.4(GRIN2A):c.2041C > T (p.Arg681Ter)	Pathogenic	Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy	[187]
CDS	GABRB3	Missense	NM_021912.4(GABRB3):c.745C > A (p.Gln249Lys)	Pathogenic	Early infantile epileptic encephalopathy (EIEE)	[188]
CDS	WDR62	Deletion/frameshift	NM_001083961.1(WDR62):c.3839_3855del17 (p.Gly1280Alafs)	Pathogenic	Malformations of cortical development	[189]
3′ UTR	MECP2	SNV	NM_004992.3(MECP2):c.*2956G > A	Uncertain significance	Rett syndrome	[190]
Promoter	CRH	SNV	NC_000008.11:g.66178947G > T	Pathogenic	Familial autosomal dominant nocturnal frontal lobe epilepsy	[191]
Splice site	ATP6AP2	SNV	NM_005765.2(ATP6AP2):c.321C > T (p.Asp107=)	Pathogenic	X-linked mental retardation and epilepsy due to inefficient inclusion of exon 4	[192]
Poly(A)	ARSA	SNV	NM_000487.5(ARSA):c.*96A > G	Pathogenic	Metachromatic leukodystrophy	[193]
NMD	SNRPB	SNV	NM_003091.3(SNRPB):c.-72C > A	Pathogenic	Cerebro-costo-mandibular syndrome	[194]
lncRNA	ATXN8OS	Insertion	NR_002717.2(ATXN8OS):n.1103_1105CTG(15_40)	Pathogenic	Spinocerebellar ataxia type 8	[195]

ACMG American College of Medical Genetics and Genomics, CDS coding sequence, HGVS Human Genome Variation Society, lncRNA long non-coding RNA, NMD nonsense-mediated decay, SNV single-nucleotide variant, UTR untranslated region

ISSN: 1756-994X