rs483352908
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152419.3(HGSNAT):c.234+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000252 in 1,546,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
HGSNAT
NM_152419.3 splice_donor, intron
NM_152419.3 splice_donor, intron
Scores
3
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.71
Genes affected
HGSNAT (HGNC:26527): (heparan-alpha-glucosaminide N-acetyltransferase) This gene encodes a lysosomal acetyltransferase, which is one of several enzymes involved in the lysosomal degradation of heparin sulfate. Mutations in this gene are associated with Sanfilippo syndrome C, one type of the lysosomal storage disease mucopolysaccaridosis III, which results from impaired degradation of heparan sulfate. [provided by RefSeq, Jan 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-43147064-G-A is Pathogenic according to our data. Variant chr8-43147064-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43147064-G-A is described in Lovd as [Pathogenic]. Variant chr8-43147064-G-A is described in Lovd as [Pathogenic]. Variant chr8-43147064-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HGSNAT | ENST00000379644.9 | c.234+1G>A | splice_donor_variant, intron_variant | 2 | NM_152419.3 | ENSP00000368965.4 | ||||
| HGSNAT | ENST00000520704.1 | n.84+1G>A | splice_donor_variant, intron_variant | 1 | ENSP00000429109.1 | |||||
| HGSNAT | ENST00000517319.1 | n.234+1G>A | splice_donor_variant, intron_variant | 4 | ENSP00000430032.1 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000469 AC: 11AN: 234654Hom.: 0 AF XY: 0.0000472 AC XY: 6AN XY: 127242
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GnomAD4 exome AF: 0.0000265 AC: 37AN: 1394402Hom.: 0 Cov.: 23 AF XY: 0.0000258 AC XY: 18AN XY: 696520
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GnomAD4 genome 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74276
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | HGSNAT: PVS1, PM2, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 31, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | May 22, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2023 | Observed with a pathogenic variant on the opposite allele (in trans) in a patient with MPSIIIC, in the published literature (Huh et al., 2013); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20825431, 25525159, 26350204, 28101780, 18024218, 25491247, 27491071, 17397050, 20583299, 19823584, 29981367, 17033958, 31589614, 31228227, 33673364, 23301227) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Mucopolysaccharidosis, MPS-III-C Pathogenic:3
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 10, 2021 | NM_152419.2(HGSNAT):c.234+1G>A is a canonical splice variant classified as pathogenic in the context of mucopolysaccharidosis type IIIC. c.234+1G>A has been observed in cases with relevant disease (PMID: 31228227, 28101780, 25491247, 17033958, 20825431, 23301227, 18024218, 17397050, 27243974, 19823584). Functional assessments of this variant are available in the literature (PMID: 25491247, 20825431). c.234+1G>A has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, NM_152419.2(HGSNAT):c.234+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 27, 2020 | - - |
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This sequence change affects a donor splice site in intron 2 of the HGSNAT gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs483352908, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis type IIIC (PMID: 17033958, 18024218, 19823584, 20825431, 23301227). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Spanish and Moroccan ancestry (PMID: 18024218, 20825431). ClinVar contains an entry for this variant (Variation ID: 30832). Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 20825431). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 05, 2024 | - - |
Sanfilippo syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 17, 2019 | Variant summary: HGSNAT c.234+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that supports these predictions (Matos_2014). The variant allele was found at a frequency of 4.7e-05 in 232180 control chromosomes (gnomAD). c.234+1G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C)(Ruijter_2008, Matos_2014), which homozygous patients were found to have a significant decrease in enzyme activity (Ruijter_2008). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Retinal dystrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Apr 11, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
GERP RS
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_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at