rs758785463

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000263.4(NAGLU):​c.343C>G​(p.Pro115Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,342,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P115S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

5
4
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.68

Publications

0 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-42536615-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NAGLUNM_000263.4 linkc.343C>G p.Pro115Ala missense_variant Exon 1 of 6 ENST00000225927.7 NP_000254.2 P54802A0A140VJE4
NAGLUXM_024450771.2 linkc.343C>G p.Pro115Ala missense_variant Exon 1 of 7 XP_024306539.1
NAGLUXM_047436138.1 linkc.-119C>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
NAGLUENST00000225927.7 linkc.343C>G p.Pro115Ala missense_variant Exon 1 of 6 1 NM_000263.4 ENSP00000225927.1 P54802
NAGLUENST00000586516.5 linkc.92C>G p.Ala31Gly missense_variant Exon 1 of 4 2 ENSP00000467135.1 K7ENX5
NAGLUENST00000591587.1 linkc.86C>G p.Ala29Gly missense_variant Exon 1 of 4 5 ENSP00000467836.1 K7EQH9
ENSG00000266929ENST00000585572.1 linkn.106C>G non_coding_transcript_exon_variant Exon 1 of 5 4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.45e-7
AC:
1
AN:
1342270
Hom.:
0
Cov.:
30
AF XY:
0.00000151
AC XY:
1
AN XY:
661966
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
27150
American (AMR)
AF:
0.00
AC:
0
AN:
30078
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23638
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30876
South Asian (SAS)
AF:
0.00
AC:
0
AN:
74744
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
32900
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4836
European-Non Finnish (NFE)
AF:
9.41e-7
AC:
1
AN:
1062210
Other (OTH)
AF:
0.00
AC:
0
AN:
55838
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.23
CADD
Uncertain
24
DANN
Uncertain
0.99
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.25
T
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.90
D
PhyloP100
1.7
Sift4G
Pathogenic
0.0
D
MVP
0.96
ClinPred
0.99
D
GERP RS
4.5
PromoterAI
-0.015
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.74
Mutation Taster
=69/31
polymorphism

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

Other links and lift over

dbSNP: rs758785463; hg19: chr17-40688633; API