rs118204025
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000263.4(NAGLU):āc.942C>Gā(p.Phe314Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,792 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 Pathogenic (ā ).
Frequency
Genomes: not found (cov: 31)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
NAGLU
NM_000263.4 missense
NM_000263.4 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 3.25
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 17-42541127-C-G is Pathogenic according to our data. Variant chr17-42541127-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1570.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.942C>G | p.Phe314Leu | missense_variant | 5/6 | ENST00000225927.7 | NP_000254.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.942C>G | p.Phe314Leu | missense_variant | 5/6 | 1 | NM_000263.4 | ENSP00000225927.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251356Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135856
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461792Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727206
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GnomAD4 genome Cov.: 31
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31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
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 12, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 314 of the NAGLU protein (p.Phe314Leu). This variant is present in population databases (rs118204025, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IIIB (PMID: 12202988, 27243974). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1570). 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 95%. For these reasons, this variant has been classified as Pathogenic. - |
NAGLU-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 14, 2023 | The NAGLU c.942C>G variant is predicted to result in the amino acid substitution p.Phe314Leu. This variant has been reported in the homozygous state or with a second NAGLU variant in individuals with mucopolysaccharidosis type IIIB (Supplementary Table S2, Yubero et al. 2016. PubMed ID: 27243974; Tanaka et al. 2002. PubMed ID: 12202988). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-40693145-C-G). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Loss of sheet (P = 0.1158);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at