chr5-74720617-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000521.4(HEXB):c.1509-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000381 in 1,602,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000521.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 250940Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135668
GnomAD4 exome AF: 0.0000414 AC: 60AN: 1450582Hom.: 0 Cov.: 28 AF XY: 0.0000388 AC XY: 28AN XY: 722404
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74288
ClinVar
Submissions by phenotype
Sandhoff disease Pathogenic:6
This sequence change falls in intron 12 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 8 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs201580118, gnomAD 0.01%). This variant has been observed in individual(s) with Sandhoff disease (PMID: 2522450, 17015493, 22789865, 24915922; Invitae). ClinVar contains an entry for this variant (Variation ID: 527971). Studies have shown that this variant results in the activation of a cryptic splice site in intron 12 (PMID: 2522450). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: HEXB c.1509-26G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Nakano_1989). The variant allele was found at a frequency of 4.9e-05 in 245836 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (4.9e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.1509-26G>A, has been reported in the literature in multiple individuals affected with Sandhoff Disease, homozygotes and compound heterozygotes (Delnooz_2009, Gort_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Delnooz_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic and uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:2
Published functional studies demonstrate a damaging effect resulting from abnormal splicing and a longer protein (Nakano et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS12-26; This variant is associated with the following publications: (PMID: 23046579, 2522450, 24915922, 17015493, 22789865, 2147031, 2170400, 1386607, 2147027, 27021291, 20798201) -
HEXB: PM2, PM3, PP3, PP4, PS3:Supporting -
Inborn genetic diseases Pathogenic:1
The c.1509-26G>A intronic alteration results from a G to A substitution 26 nucleotides before coding exon 13 of the HEXB gene. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (12/250940) total alleles studied. The highest observed frequency was 0.01% (12/113452) of European (non-Finnish) alleles. This alteration has been reported in association with Sandhoff disease in homozygotes and in heterozygotes with an additional HEXB variant (Maegawa, 2006; Delnooz, 2010; Gort, 2012; Zhang 2016). Experimental evidence suggests this alteration has an impact on splicing resulting in an in-frame insertion of 24 nucleotides and 8 amino acids (Nakano, 1989). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -
Sandhoff disease, juvenile form Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at