rs1555621442

Variant names:

• chr17-42536480-G-GGCGGC
• rs1555621442
• NM_000263.4:c.217_221dupGCGCG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000263.4(NAGLU):​c.217_221dupGCGCG​(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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: NAGLU NM_000263.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.55

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]

ENSG00000266929 (HGNC:):

ACMG classification

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 17-42536480-G-GGCGGC is Pathogenic according to our data. Variant chr17-42536480-G-GGCGGC is described in ClinVar as [Pathogenic]. Clinvar id is 556349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGLU	NM_000263.4	c.217_221dupGCGCG	p.Val75ArgfsTer49	frameshift_variant	Exon 1 of 6	ENST00000225927.7	NP_000254.2
NAGLU	XM_024450771.2	c.217_221dupGCGCG	p.Val75ArgfsTer49	frameshift_variant	Exon 1 of 7		XP_024306539.1
NAGLU	XM_047436138.1	c.-245_-241dupGCGCG		5_prime_UTR_variant	Exon 1 of 5		XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7	c.217_221dupGCGCG	p.Val75ArgfsTer49	frameshift_variant	Exon 1 of 6	1	NM_000263.4	ENSP00000225927.1
NAGLU	ENST00000586516.5	c.-44_-43insGCGGC		upstream_gene_variant		2		ENSP00000467135.1
NAGLU	ENST00000591587.1	c.-50_-49insGCGGC		upstream_gene_variant		5		ENSP00000467836.1
ENSG00000266929	ENST00000585572.1	n.-30_-29insGCGGC		upstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000188 AC: 2 AN: 1064384 Hom.: 0 Cov.: 30 AF XY: 0.00000392 AC XY: 2 AN XY: 510232

Gnomad4 AFR exome AF: 0.0000470

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000110

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10094189, 20852935) -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-III-B Pathogenic:1

Jan 30, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:1

Dec 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555621442; hg19: chr17-40688498;