8-43161462-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_152419.3(HGSNAT):c.518G>A(p.Gly173Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
HGSNAT
NM_152419.3 missense
NM_152419.3 missense
Scores
2
6
8
Clinical Significance
Conservation
PhyloP100: 2.09
Genes affected
HGSNAT (HGNC:26527): (heparan-alpha-glucosaminide N-acetyltransferase) This gene encodes a lysosomal acetyltransferase, which is one of several enzymes involved in the lysosomal degradation of heparin sulfate. Mutations in this gene are associated with Sanfilippo syndrome C, one type of the lysosomal storage disease mucopolysaccaridosis III, which results from impaired degradation of heparan sulfate. [provided by RefSeq, Jan 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.814
PP5
Variant 8-43161462-G-A is Pathogenic according to our data. Variant chr8-43161462-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 252961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43161462-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HGSNAT | NM_152419.3 | c.518G>A | p.Gly173Asp | missense_variant | 5/18 | ENST00000379644.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HGSNAT | ENST00000379644.9 | c.518G>A | p.Gly173Asp | missense_variant | 5/18 | 2 | NM_152419.3 | P3 | |
HGSNAT | ENST00000520704.1 | c.368G>A | p.Gly123Asp | missense_variant, NMD_transcript_variant | 5/10 | 1 | |||
HGSNAT | ENST00000517319.1 | c.*87G>A | 3_prime_UTR_variant, NMD_transcript_variant | 4/5 | 4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-C Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 01, 2020 | Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PM2,PM3_Strong - |
Pathogenic, criteria provided, single submitter | clinical testing;in vitro | Charité Universitätsmedizin Berlin, Charite Universitaetsmedizin Berlin | Aug 03, 2016 | The effect of the mutation has been verified by a biochemical assay in one affected (homozygous) patient: measurement of Heparan-alpha-glucosaminide-N-acetyltransferase activity. Patient: 0.09 nmol/h*mg; controls 0.2-1.3 nmol/h*mg, n=11 - |
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HGSNAT function (PMID: 31228227). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HGSNAT protein function. ClinVar contains an entry for this variant (Variation ID: 252961). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 27827379, 31228227). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 173 of the HGSNAT protein (p.Gly173Asp). - |
Mucopolysaccharidosis Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
D
Sift4G
Benign
T
Vest4
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at