rs778021009
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000263.4(NAGLU):c.1447dupT(p.Tyr483fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000338 in 1,599,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
NAGLU
NM_000263.4 frameshift
NM_000263.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
NAGLU (HGNC:7632): (N-acetyl-alpha-glucosaminidase) This gene encodes an enzyme that degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides. Defects in this gene are the cause of mucopolysaccharidosis type IIIB (MPS-IIIB), also known as Sanfilippo syndrome B. This disease is characterized by the lysosomal accumulation and urinary excretion of heparan sulfate. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 24 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-42543452-G-GT is Pathogenic according to our data. Variant chr17-42543452-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557862.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 |
---|---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.1447dupT | p.Tyr483fs | frameshift_variant | 6/6 | ENST00000225927.7 | NP_000254.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.1447dupT | p.Tyr483fs | frameshift_variant | 6/6 | 1 | NM_000263.4 | ENSP00000225927.1 | ||
NAGLU | ENST00000591587.1 | c.*416dupT | 3_prime_UTR_variant | 4/4 | 5 | ENSP00000467836.1 | ||||
NAGLU | ENST00000592454.1 | c.*290dupT | 3_prime_UTR_variant | 2/2 | 2 | ENSP00000468665.1 | ||||
ENSG00000266929 | ENST00000585572.1 | n.379+4698dupT | intron_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152284Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000450 AC: 1AN: 222278Hom.: 0 AF XY: 0.00000826 AC XY: 1AN XY: 121074
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GnomAD4 exome AF: 0.0000359 AC: 52AN: 1446744Hom.: 0 Cov.: 32 AF XY: 0.0000431 AC XY: 31AN XY: 719030
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74398
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 13, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 06, 2020 | Variant summary: NAGLU c.1447dupT (p.Tyr483LeufsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-06 in 222278 control chromosomes. c.1447dupT has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B; e.g. Beesley_1998, Truxal_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence that cells expressing the variant had no detectable enzyme activity in-vitro (e.g. Clark_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 09, 2023 | This sequence change creates a premature translational stop signal (p.Tyr483Leufs*33) in the NAGLU gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 261 amino acid(s) of the NAGLU protein. This variant is present in population databases (rs778021009, gnomAD 0.001%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type IIIB (PMID: 9832037, 27590925). ClinVar contains an entry for this variant (Variation ID: 557862). This variant disrupts a region of the NAGLU protein in which other variant(s) (p.Arg533*) have been determined to be pathogenic (PMID: 18218046). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at