rs118204025

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The ENST00000225927.7(NAGLU):ā€‹c.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˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F314S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

NAGLU
ENST00000225927.7 missense

Scores

10
6
3

Clinical Significance

Pathogenic criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 3.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000225927.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-42541125-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1495526.Status of the report is criteria_provided_single_submitter, 1 stars.
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
NAGLUNM_000263.4 linkuse as main transcriptc.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
NAGLUENST00000225927.7 linkuse as main transcriptc.942C>G p.Phe314Leu missense_variant 5/61 NM_000263.4 ENSP00000225927 P1
NAGLUENST00000592454.1 linkuse as main transcriptc.39C>G p.Phe13Leu missense_variant 1/22 ENSP00000468665
NAGLUENST00000591587.1 linkuse as main transcriptc.360-1901C>G intron_variant 5 ENSP00000467836
NAGLUENST00000586516.5 linkuse as main transcript downstream_gene_variant 2 ENSP00000467135

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251356
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461792
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
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 providedliterature onlyOMIMJan 01, 2002- -
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 12, 2024This 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 providedclinical testingPreventionGenetics, part of Exact SciencesNov 14, 2023The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.47
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.24
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
2.9
M
MutationTaster
Benign
1.0
A
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-5.6
D
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.037
D
Polyphen
0.15
B
Vest4
1.0
MutPred
0.97
Loss of sheet (P = 0.1158);
MVP
0.90
MPC
0.97
ClinPred
0.96
D
GERP RS
1.8
Varity_R
0.78
gMVP
0.90

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.

Other links and lift over

dbSNP: rs118204025; hg19: chr17-40693145; API