chr17-42536480-G-GGCGGC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000263.4(NAGLU):c.217_221dup(p.Val75ArgfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,064,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G70G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
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.217_221dup | p.Val75ArgfsTer49 | frameshift_variant | 1/6 | ENST00000225927.7 | |
NAGLU | XM_024450771.2 | c.217_221dup | p.Val75ArgfsTer49 | frameshift_variant | 1/7 | ||
NAGLU | XM_047436138.1 | c.-245_-241dup | 5_prime_UTR_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.217_221dup | p.Val75ArgfsTer49 | frameshift_variant | 1/6 | 1 | NM_000263.4 | P1 | |
NAGLU | ENST00000586516.5 | upstream_gene_variant | 2 | ||||||
NAGLU | ENST00000591587.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000188 AC: 2AN: 1064384Hom.: 0 Cov.: 30 AF XY: 0.00000392 AC XY: 2AN XY: 510232
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Mucopolysaccharidosis, MPS-III-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 30, 2018 | - - |
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Val75Argfs*49) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type IIIB (MPS IIIB) (PMID: 10094189, 20852935). This variant is also known as ins5bp209. 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