17-42536416-C-G

Variant names:

• chr17-42536416-C-G
• rs104894599
• NM_000263.4:c.144C>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000263.4(NAGLU):​c.144C>G​(p.Phe48Leu) variant causes a missense 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F48F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 0.253
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health
• Charcot-Marie-Tooth disease axonal type 2V

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000266929 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS1: Transcript NM_000263.4 (NAGLU) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a strand (size 4) in uniprot entity ANAG_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000263.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 17-42536416-C-G is Pathogenic according to our data. Variant chr17-42536416-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 555776.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.144C>G	p.Phe48Leu	missense_variant	Exon 1 of 6	ENST00000225927.7	NP_000254.2
NAGLU	XM_047436138.1	c.-318C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5		XP_047292094.1
NAGLU	XM_024450771.2	c.144C>G	p.Phe48Leu	missense_variant	Exon 1 of 7		XP_024306539.1
NAGLU	XM_047436138.1	c.-318C>G		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.144C>G	p.Phe48Leu	missense_variant	Exon 1 of 6	1	NM_000263.4	ENSP00000225927.1
NAGLU	ENST00000586516.5	c.-108C>G		upstream_gene_variant		2		ENSP00000467135.1
NAGLU	ENST00000591587.1	c.-114C>G		upstream_gene_variant		5		ENSP00000467836.1
ENSG00000266929	ENST00000585572.1	n.-94C>G		upstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1098134 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 531702

African (AFR) AF: 0.00 AC: 0 AN: 22160

American (AMR) AF: 0.00 AC: 0 AN: 17018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16432

East Asian (EAS) AF: 0.00 AC: 0 AN: 19570

South Asian (SAS) AF: 0.00 AC: 0 AN: 37228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2938

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 919456

Other (OTH) AF: 0.00 AC: 0 AN: 42054

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Nov 29, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

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

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 48 of the NAGLU protein (p.Phe48Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 10094189). ClinVar contains an entry for this variant (Variation ID: 555776). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NAGLU protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NAGLU function (PMID: 11068184). This variant disrupts the p.Phe48 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9832037, 29979746). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Mucopolysaccharidosis, MPS-III-B Uncertain:1

Dec 21, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	0.042
Eigen_PC	Benign	-0.13
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.25
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.2	D
Sift	Benign	0.034	D
Sift4G	Benign	0.10	T
Vest4		0.74
ClinPred		1.0	D
GERP RS		3.4
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.82
gMVP		0.76

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

Other links and lift over

dbSNP: rs104894599; hg19: chr17-40688434;