rs886039894

chr17-42537493-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000263.4(NAGLU):c.480del(p.Asn160LysfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.772

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 17-42537493-AT-A is Pathogenic according to our data. Variant chr17-42537493-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 266015.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGLU	NM_000263.4	c.480del	p.Asn160LysfsTer25	frameshift_variant	2/6	ENST00000225927.7
NAGLU	XM_024450771.2	c.537del	p.Asn179LysfsTer25	frameshift_variant	3/7
NAGLU	XM_047436138.1	c.-79+839del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGLU	ENST00000225927.7	c.480del	p.Asn160LysfsTer25	frameshift_variant	2/6	1	NM_000263.4	P1
NAGLU	ENST00000590358.1	c.168del	p.Asn56LysfsTer25	frameshift_variant	1/2	4
NAGLU	ENST00000586516.5	c.133+839del		intron_variant		2
NAGLU	ENST00000591587.1	c.126+839del		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Nov 07, 2017

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 23, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 266015). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis (PMID: 28844463). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn160Lysfs*25) 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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039894; hg19: chr17-40689511;