rs200926928
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000520.6(HEXA):c.986+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000291 in 1,612,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
HEXA
NM_000520.6 splice_region, intron
NM_000520.6 splice_region, intron
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 5.95
Genes affected
HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-72349076-T-C is Pathogenic according to our data. Variant chr15-72349076-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HEXA | NM_000520.6 | c.986+3A>G | splice_region_variant, intron_variant | ENST00000268097.10 | NP_000511.2 | |||
| HEXA | NM_001318825.2 | c.1019+3A>G | splice_region_variant, intron_variant | NP_001305754.1 | ||||
| HEXA | NR_134869.3 | n.1028+3A>G | splice_region_variant, intron_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HEXA | ENST00000268097.10 | c.986+3A>G | splice_region_variant, intron_variant | 1 | NM_000520.6 | ENSP00000268097.6 | ||||
| ENSG00000260729 | ENST00000379915.4 | n.413-2751A>G | intron_variant | 2 | ENSP00000478716.1 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251270Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135818
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1460678Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 726738
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GnomAD4 genome 0.0000460 AC: 7AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74492
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tay-Sachs disease Pathogenic:7
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 16, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 12, 2023 | The c.1019+3A>G variant in HEXA (also reported as c.986+3A>G in the literature) has been reported in the compound heterozygous state in at least 3 individuals with Tay-Sachs disease and in the heterozygous state in 1 individual where a second HEXA allele was not identified (Richard 1995 PMID: 7551830, Giraud 2010 PMID: 20100466, Saunders 2012 PMID: 23035047, Jamali 2014 PMID: 24518553). This variant has also been reported in by other clinical laboratories in ClinVar (Variation ID: 188929) and been identified in 0.007% (5/68032) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is located in the 3' splice region. Computational tools predict a splicing impact, and functional studies confirm skipping of exon 8 leading to a premature stop codon which is predicted to result in an abnormal or absent protein (Richard 1995 PMID: 7551830). Biallelic loss of function of the HEXA gene is an established disease mechanism in autosomal recessive Tay-Sachs disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Tay-Sachs disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting. - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 21, 2014 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 13, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 08, 2017 | The HEXA c.986+3A>G splice region variant has been reported in at least four studies in which it is found in a total of three patients in a compound heterozygous state and in a heterozygous state in one obligate carrier (Richard et al. 1995; Akerman et al. 1997; Giraud et al. 2010; Saunders et al. 2012). One compound heterozygote presented with the late-infantile onset form of Tay-Sachs disease while another compound heterozygote had onset in adulthood. Control data are unavailable for this variant which is reported at a frequency of 0.000025 in the total population from the Exome Aggregation Consortium. In one study, exons 7 to 9 of the c.986+3A>G variant HEXA were amplified and the resulting mRNA product was shown to be lacking exon 8, suggesting this variant affects splicing (Richard et al. 1995). Based on the evidence, the c.986+3A>G variant is classified as likely pathogenic for hexoaminidase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2018 | Variant summary: HEXA c.986+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. A publication, Richard_1995, functionally assessed the variant and found it to cause exon 8 to be deleted, which is located in the Glycoside hydrolase family 20, catalytic domain (via InterPro). The variant was observed with an allele frequency of 8.1e-06 in 246182 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (8.1e-06 vs 0.0014), allowing no conclusion about variant significance. The variant, c.986+3A>G, has been reported in the literature in individuals affected with Tay-Sachs Disease. These data indicate that the variant is likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change falls in intron 8 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs200926928, gnomAD 0.01%). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 7551830, 23035047, 24518553). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188929). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8 and introduces a premature termination codon (PMID: 7551830). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
HEXA-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 06, 2024 | The HEXA c.986+3A>G variant is predicted to interfere with splicing. This variant has been reported in individuals with Tay-Sachs disease (Richard et al. 1995. PubMed ID: 7551830; Table 2, Akerman et al. 1997. PubMed ID: 9150157; Table 1, Giraud et al. 2010. PubMed ID: 20100466; Saunders et al. 2012. PubMed ID: 23035047). Splicing assays also reveal this variant results in exclusion of exon 8 (Richard et al. 1995. PubMed ID: 7551830). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2023 | Published functional studies demonstrate the variant a damaging effect on splicing of HEXA mRNA (Richard et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 9150157, 24518553, 20100466, 29790872, 7551830, 23035047) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
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DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at