rs778021009
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000263.4(NAGLU):c.1447dup(p.Tyr483LeufsTer33) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R482R) has been classified as Likely benign.
Frequency
Consequence
NM_000263.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.1447dup | p.Tyr483LeufsTer33 | frameshift_variant | 6/6 | ENST00000225927.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.1447dup | p.Tyr483LeufsTer33 | frameshift_variant | 6/6 | 1 | NM_000263.4 | P1 | |
NAGLU | ENST00000591587.1 | c.*416dup | 3_prime_UTR_variant | 4/4 | 5 | ||||
NAGLU | ENST00000592454.1 | c.*290dup | 3_prime_UTR_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152284Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000450 AC: 1AN: 222278Hom.: 0 AF XY: 0.00000826 AC XY: 1AN XY: 121074
GnomAD4 exome AF: 0.0000359 AC: 52AN: 1446744Hom.: 0 Cov.: 32 AF XY: 0.0000431 AC XY: 31AN XY: 719030
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74398
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 13, 2018 | - - |
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at