dbSNP rs1431589133: NAGLU:p.Arg74ProfsTer42 (chr17-42536483-GGCGCGGCGCGCGTGCGGGT-G) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000263.4(NAGLU):c.219_237delGCGCGTGCGGGTGCGCGGC(p.Arg74ProfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,067,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.44

Variant links:

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]

NAGLU links:

ENSG00000266929 (HGNC:):

ENSG00000266929 links:

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ACMG classification

Classification made for transcript

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 17-42536483-GGCGCGGCGCGCGTGCGGGT-G is Pathogenic according to our data. Variant chr17-42536483-GGCGCGGCGCGCGTGCGGGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554876.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 link	c.219_237delGCGCGTGCGGGTGCGCGGC	p.Arg74ProfsTer42	frameshift_variant	Exon 1 of 6	ENST00000225927.7	NP_000254.2	P54802A0A140VJE4
NAGLU	XM_024450771.2 link	c.219_237delGCGCGTGCGGGTGCGCGGC	p.Arg74ProfsTer42	frameshift_variant	Exon 1 of 7		XP_024306539.1
NAGLU	XM_047436138.1 link	c.-243_-225delGCGCGTGCGGGTGCGCGGC		5_prime_UTR_variant	Exon 1 of 5		XP_047292094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NAGLU	ENST00000225927.7 link	c.219_237delGCGCGTGCGGGTGCGCGGC	p.Arg74ProfsTer42	frameshift_variant	Exon 1 of 6	1	NM_000263.4	ENSP00000225927.1	P54802
NAGLU	ENST00000586516.5 link	c.-40_-22delGCGCGGCGCGCGTGCGGGT		upstream_gene_variant		2		ENSP00000467135.1	K7ENX5
NAGLU	ENST00000591587.1 link	c.-46_-28delGCGCGGCGCGCGTGCGGGT		upstream_gene_variant		5		ENSP00000467836.1	K7EQH9
ENSG00000266929	ENST00000585572.1 link	n.-26_-8delGCGCGGCGCGCGTGCGGGT		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000861

AC:

AN:

11614

Hom.:

AF XY:

0.000129

AC XY:

AN XY:

7756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000192

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1067176

Hom.:

AF XY:

0.0000117

AC XY:

AN XY:

511482

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000120

Gnomad4 OTH exome

AF:

0.0000241

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B

Pathogenic:2

Feb 25, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2017

Counsyl

Significance: Likely 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

Sep 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 554876). This premature translational stop signal has been observed in individual(s) with NAGLU-related conditions (PMID: 9832037). This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg74Profs*42) 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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over