17-42544122-C-T

Position:

chr17-42544122-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_000263.4(NAGLU):c.2116C>T(p.Gln706*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,012 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: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 0.714

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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. Fraction of 0.052 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-42544122-C-T is Pathogenic according to our data. Variant chr17-42544122-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553260.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGLU	NM_000263.4 linkuse as main transcript	c.2116C>T	p.Gln706*	stop_gained	6/6	ENST00000225927.7	NP_000254.2	P54802A0A140VJE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NAGLU	ENST00000225927.7 linkuse as main transcript	c.2116C>T	p.Gln706*	stop_gained	6/6	1	NM_000263.4	ENSP00000225927.1	P54802
NAGLU	ENST00000591587.1 linkuse as main transcript	c.*1085C>T		3_prime_UTR_variant	4/4	5		ENSP00000467836.1	K7EQH9
ENSG00000266929	ENST00000585572.1 linkuse as main transcript	n.379+5367C>T		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251326

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135862

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:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727214

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:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2020	Variant summary: NAGLU c.2116C>T (p.Gln706X) results in a premature termination codon in the last exon (exon 6) of the NAGLU gene and predicted to cause a truncation of the encoded protein. The variant allele was found at a frequency of 8e-06 in 251326 control chromosomes. c.2116C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and subsequently cited by others (example, Zhao_1998, Whitley_2018, Schmidtchen_1998, Yogalingam_2001, Jain_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal NAGLU enzyme activity and elevated urine glycosaminoglycan (GAG) and cerebrospinal fluid heparan sulfate levels (example, Whitley_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing at-least one overlapping publication utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 17, 2021	NM_000263.3(NAGLU):c.2116C>T(Q706) is a nonsense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIB. Q706 has been observed in cases with relevant disease (PMID: 9443875, 29661560). Functional assessments of this variant are not available in the literature. Q706* has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, there is insufficient evidence to classify NM_000263.3(NAGLU):c.2116C>T(Q706*) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

NAGLU-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2023

The NAGLU c.2116C>T variant is predicted to result in premature protein termination (p.Gln706*). This variant was reported in homozygous and compound heterozygous state an individuals with Sanfilippo syndrome B, also known as Mucopolysaccharidosis IIIB (Zhao et al. 1998. PubMed ID: 9443875; Whitley et al. 2018. PubMed ID: 29661560). This variant occurs within the last exon and is not predicted to result in nonsense mediated decay, however pathogenic variants upstream and downstream have been reported. This variant is reported in 0.0015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-40696140-C-T). This variant is interpreted as likely pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Gln706*) in the NAGLU gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the NAGLU protein. This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Sanfilippo syndrome B (PMID: 9443875, 29661560). ClinVar contains an entry for this variant (Variation ID: 553260). This variant disrupts a region of the NAGLU protein in which other variant(s) (p.Lys729del) have been observed in individuals with NAGLU-related conditions (PMID: 22976768). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.76

Vest4

0.59

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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