rs762031686

Positions:

• chr17-42543680-C-G
• chr17-42543680-C-T

Variant summary

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

The ENST00000225927.7(NAGLU):​c.1674C>G​(p.Tyr558Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y558Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NAGLU ENST00000225927.7 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.75

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 65 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-42543680-C-G is Pathogenic according to our data. Variant chr17-42543680-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42543680-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGLU	NM_000263.4	c.1674C>G	p.Tyr558Ter	stop_gained	6/6	ENST00000225927.7	NP_000254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7	c.1674C>G	p.Tyr558Ter	stop_gained	6/6	1	NM_000263.4	ENSP00000225927	P1
NAGLU	ENST00000591587.1	c.*643C>G		3_prime_UTR_variant	4/4	5		ENSP00000467836

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

May 23, 2018

- -

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

Jan 13, 2023

ClinVar contains an entry for this variant (Variation ID: 558459). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NAGLU protein in which other variant(s) (p.Val724Glyfs*32) have been determined to be pathogenic (PMID: 10094189; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 21910976). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr558*) in the NAGLU gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 186 amino acid(s) of the NAGLU protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	20
DANN	Benign	0.97
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.45	N
MutationTaster	Benign	1.0	D
Vest4		0.85
GERP RS		-8.0

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: rs762031686; hg19: chr17-40695698;