rs753355844

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_152419.3(HGSNAT):c.1411G>A(p.Glu471Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,608 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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.46

Variant links:

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]

HGSNAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a topological_domain Lumenal, vesicle (size 58) in uniprot entity HGNAT_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_152419.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 8-43193790-G-A is Pathogenic according to our data. Variant chr8-43193790-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43193790-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3 link	c.1411G>A	p.Glu471Lys	missense_variant	Exon 14 of 18	ENST00000379644.9	NP_689632.2	Q68CP4-2Q8IVU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HGSNAT	ENST00000379644.9 link	c.1411G>A	p.Glu471Lys	missense_variant	Exon 14 of 18	2	NM_152419.3	ENSP00000368965.4	Q68CP4-2
HGSNAT	ENST00000521576.1 link	c.562G>A	p.Glu188Lys	missense_variant	Exon 5 of 9	2		ENSP00000429029.1	E5RJN0
HGSNAT	ENST00000524016.5 link	c.514G>A	p.Glu172Lys	missense_variant	Exon 5 of 7	4		ENSP00000428322.1	H0YAZ0
HGSNAT	ENST00000520678.1 link	n.344G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249268

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135222

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727094

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000363

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C

Pathogenic:2

Feb 13, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73

Pathogenic:2

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 471 of the HGSNAT protein (p.Glu471Lys). This variant is present in population databases (rs753355844, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 17033958, 18024218, 19479962). This variant is also known as p.E499K. ClinVar contains an entry for this variant (Variation ID: 265483). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects HGSNAT function (PMID: 20583299). For these reasons, this variant has been classified as Pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 73

Pathogenic:1

Oct 10, 2020

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate the variant causes negligible heparan acetyl CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) enzyme activity and caused misfolding of the HGSNAT protein and retention in the endoplasmic reticulum (PMID: 20583299, PMID: 19823584); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17033958, 19823584, 18024218, 19479962, 32770643, 31228227, 31964843, 20583299) -

Sanfilippo syndrome

Pathogenic:1

Jun 05, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The HGSNAT c.1411G>A (p.Glu471Lys) variant causes the change of "an acidic residue for a basic one just inside the lysosomal luman (Feldhammer_2009)" involving the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant . This variant was found in 1/120760 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic HGSNAT variant (0.001). The variant was reported in the literature in MPS type IIIC patients both in the homozygous state and in the compound heterozygous state with other pathogenic variants. Additionally, the variant expressed in various cell model systems was shown to have significantly decreased enzyme activity, and to result in production of misfolded HGSNAT protein that is abnormally glycosylated and not targeted to the lysosome (Fedele_2010, Feldhammer_2009). One clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.21

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.95

MVP

0.89

MPC

0.55

ClinPred

1.0

GERP RS

5.1

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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