rs398123281
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000263.4(NAGLU):c.503G>A(p.Trp168Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 35)
Consequence
NAGLU
NM_000263.4 stop_gained
NM_000263.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.18
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-42537517-G-A is Pathogenic according to our data. Variant chr17-42537517-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42537517-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.503G>A | p.Trp168Ter | stop_gained | 2/6 | ENST00000225927.7 | |
NAGLU | XM_024450771.2 | c.560G>A | p.Trp187Ter | stop_gained | 3/7 | ||
NAGLU | XM_047436138.1 | c.-78-822G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.503G>A | p.Trp168Ter | stop_gained | 2/6 | 1 | NM_000263.4 | P1 | |
NAGLU | ENST00000590358.1 | c.191G>A | p.Trp64Ter | stop_gained | 1/2 | 4 | |||
NAGLU | ENST00000586516.5 | c.134-822G>A | intron_variant | 2 | |||||
NAGLU | ENST00000591587.1 | c.127-822G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 35
GnomAD3 genomes
?
Cov.:
35
GnomAD4 exome Cov.: 56
GnomAD4 exome
Cov.:
56
GnomAD4 genome ? Cov.: 35
GnomAD4 genome
?
Cov.:
35
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 26, 2022 | Variant summary: NAGLU c.503G>A (p.Trp168X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251134 control chromosomes. c.503G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (example, Coll_2001, Mangas_2008). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 29, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 09, 2012 | - - |
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | ClinVar contains an entry for this variant (Variation ID: 92695). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 11286389, 18218046). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp168*) in the NAGLU gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NAGLU are known to be pathogenic (PMID: 9832037, 10094189, 16151907). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at