rs747240928

Variant summary

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

The NM_152419.3(HGSNAT):​c.1516C>T​(p.Arg506Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,611,404 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.187
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-43196999-C-T is Pathogenic according to our data. Variant chr8-43196999-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 552134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43196999-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HGSNATNM_152419.3 linkuse as main transcriptc.1516C>T p.Arg506Ter stop_gained 15/18 ENST00000379644.9 NP_689632.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HGSNATENST00000379644.9 linkuse as main transcriptc.1516C>T p.Arg506Ter stop_gained 15/182 NM_152419.3 ENSP00000368965 P3Q68CP4-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248672
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134884
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:
0.0000329
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1459246
Hom.:
0
Cov.:
28
AF XY:
0.00000826
AC XY:
6
AN XY:
726098
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Dec 29, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCounsylMay 23, 2017- -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pediatrics, Taizhou Central Hospital, Taizhou University HospitalFeb 01, 2024- -
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 07, 2023For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 552134). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type III C (PMID: 17033958). This variant is present in population databases (rs747240928, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg506*) in the HGSNAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HGSNAT are known to be pathogenic (PMID: 17033958, 19479962). -
Retinitis pigmentosa 73 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterSep 24, 2024Criteria applied: PVS1,PM3,PM2_SUP -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 15, 2020Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21384162, 19479962, 17033958, 25525159) -
Sanfilippo syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 31, 2022Variant summary: HGSNAT c.1516C>T (p.Arg506X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 248672 control chromosomes (gnomAD). c.1516C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C; Feldhammer_2009, Hrebicek_2006, Pervaiz_2011, Martins_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
29
DANN
Uncertain
0.98
Eigen
Benign
0.028
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.21
N
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.95
ClinPred
0.98
D
GERP RS
-0.43

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: rs747240928; hg19: chr8-43052142; API