chr17-42537493-AT-A

Position:

• 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	Protein	UniProt
NAGLU	NM_000263.4	c.480del	p.Asn160LysfsTer25	frameshift_variant	2/6	ENST00000225927.7	NP_000254.2
NAGLU	XM_024450771.2	c.537del	p.Asn179LysfsTer25	frameshift_variant	3/7		XP_024306539.1
NAGLU	XM_047436138.1	c.-79+839del		intron_variant			XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7	c.480del	p.Asn160LysfsTer25	frameshift_variant	2/6	1	NM_000263.4	ENSP00000225927	P1
NAGLU	ENST00000590358.1	c.168del	p.Asn56LysfsTer25	frameshift_variant	1/2	4		ENSP00000466892
NAGLU	ENST00000586516.5	c.133+839del		intron_variant		2		ENSP00000467135
NAGLU	ENST00000591587.1	c.126+839del		intron_variant		5		ENSP00000467836

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

Labcorp Genetics (formerly Invitae), Labcorp

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;