chr17-42544119-G-A

Position:

• chr17-42544119-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000263.4(NAGLU):​c.2113G>A​(p.Glu705Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 7.97

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 17-42544119-G-A is Pathogenic according to our data. Variant chr17-42544119-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554624.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGLU	NM_000263.4	c.2113G>A	p.Glu705Lys	missense_variant	6/6	ENST00000225927.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGLU	ENST00000225927.7	c.2113G>A	p.Glu705Lys	missense_variant	6/6	1	NM_000263.4	P1
NAGLU	ENST00000591587.1	c.*1082G>A		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251326 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Mucopolysaccharidosis, MPS-III-B Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Oct 27, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2024	Variant summary: NAGLU c.2113G>A (p.Glu705Lys) results in a conservative amino acid change located in the alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) of the encoded protein sequence. Structural studies have predicted that this alters the secondary structure of the NAGLU protein (Birrane_2019). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251326 control chromosomes (gnomAD). c.2113G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (example, Beesley_1998) who was diagnosed with the severe form of the disease with a NAGLU enzyme activity of <0.1 nmol/h/mg protein in white blood cells. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9832037, 30802506). ClinVar contains an entry for this variant (Variation ID: 554624). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Jul 03, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 554624). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 9832037; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 705 of the NAGLU protein (p.Glu705Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.92
Sift	Benign	0.036	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.73
MVP		0.99
MPC		1.2
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.93
gMVP		0.96

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: rs1364203992; hg19: chr17-40696137;