rs483352908

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_152419.3(HGSNAT):c.234+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000252 in 1,546,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.71

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 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-43147064-G-A is Pathogenic according to our data. Variant chr8-43147064-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43147064-G-A is described in Lovd as [Pathogenic]. Variant chr8-43147064-G-A is described in Lovd as [Pathogenic]. Variant chr8-43147064-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3 link	c.234+1G>A		splice_donor_variant, intron_variant	Intron 2 of 17	ENST00000379644.9	NP_689632.2	Q68CP4-2Q8IVU6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HGSNAT	ENST00000379644.9 link	c.234+1G>A	splice_donor_variant, intron_variant	Intron 2 of 17	2	NM_152419.3	ENSP00000368965.4	Q68CP4-2
HGSNAT	ENST00000520704.1 link	n.84+1G>A	splice_donor_variant, intron_variant	Intron 2 of 9	1		ENSP00000429109.1	E5RJC4
HGSNAT	ENST00000517319.1 link	n.234+1G>A	splice_donor_variant, intron_variant	Intron 2 of 4	4		ENSP00000430032.1	E5RH11

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000469

AC:

AN:

234654

Hom.:

AF XY:

0.0000472

AC XY:

AN XY:

127242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000199

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000593

Gnomad SAS exome

AF:

0.0000378

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000275

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000265

AC:

AN:

1394402

Hom.:

Cov.:

AF XY:

0.0000258

AC XY:

AN XY:

696520

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000172

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000255

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 22, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HGSNAT: PVS1, PM2, PS3:Supporting -

Jan 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a pathogenic variant on the opposite allele (in trans) in a patient with MPSIIIC, in the published literature (Huh et al., 2013); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20825431, 25525159, 26350204, 28101780, 18024218, 25491247, 27491071, 17397050, 20583299, 19823584, 29981367, 17033958, 31589614, 31228227, 33673364, 23301227) -

Mucopolysaccharidosis, MPS-III-C

Pathogenic:3

Oct 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 27, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 10, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_152419.2(HGSNAT):c.234+1G>A is a canonical splice variant classified as pathogenic in the context of mucopolysaccharidosis type IIIC. c.234+1G>A has been observed in cases with relevant disease (PMID: 31228227, 28101780, 25491247, 17033958, 20825431, 23301227, 18024218, 17397050, 27243974, 19823584). Functional assessments of this variant are available in the literature (PMID: 25491247, 20825431). c.234+1G>A has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, NM_152419.2(HGSNAT):c.234+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

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

Pathogenic:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 2 of the HGSNAT gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs483352908, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis type IIIC (PMID: 17033958, 18024218, 19823584, 20825431, 23301227). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Spanish and Moroccan ancestry (PMID: 18024218, 20825431). ClinVar contains an entry for this variant (Variation ID: 30832). Studies have shown that disruption of this splice site results in skipping of exon 2, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20825431). For these reasons, this variant has been classified as Pathogenic. -

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sanfilippo syndrome

Pathogenic:1

Jan 17, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HGSNAT c.234+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that supports these predictions (Matos_2014). The variant allele was found at a frequency of 4.7e-05 in 232180 control chromosomes (gnomAD). c.234+1G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C)(Ruijter_2008, Matos_2014), which homozygous patients were found to have a significant decrease in enzyme activity (Ruijter_2008). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy

Pathogenic:1

Apr 11, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.89

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

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