NM_152419.3:c.525dupT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152419.3(HGSNAT):c.525dupT(p.Val176CysfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
HGSNAT
NM_152419.3 frameshift
NM_152419.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -5.34
Publications
4 publications found
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 Gene-Disease associations (from GenCC):
- inherited retinal dystrophyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- mucopolysaccharidosis type 3Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
- mucopolysaccharidosis type 3CInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- retinitis pigmentosa 73Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- retinitis pigmentosaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 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 8-43161468-C-CT is Pathogenic according to our data. Variant chr8-43161468-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 1235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_152419.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HGSNAT | NM_152419.3 | MANE Select | c.525dupT | p.Val176CysfsTer16 | frameshift | Exon 5 of 18 | NP_689632.2 | ||
| HGSNAT | NM_001363227.2 | c.525dupT | p.Val176CysfsTer16 | frameshift | Exon 5 of 19 | NP_001350156.1 | |||
| HGSNAT | NM_001363228.2 | c.525dupT | p.Val176CysfsTer16 | frameshift | Exon 5 of 16 | NP_001350157.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HGSNAT | ENST00000379644.9 | TSL:2 MANE Select | c.525dupT | p.Val176CysfsTer16 | frameshift | Exon 5 of 18 | ENSP00000368965.4 | Q68CP4-2 | |
| HGSNAT | ENST00000520704.1 | TSL:1 | n.375dupT | non_coding_transcript_exon | Exon 5 of 10 | ENSP00000429109.1 | E5RJC4 | ||
| HGSNAT | ENST00000902460.1 | c.525dupT | p.Val176CysfsTer16 | frameshift | Exon 5 of 19 | ENSP00000572519.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459690Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726078 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
3
AN:
1459690
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
726078
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33380
American (AMR)
AF:
AC:
0
AN:
44500
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26104
East Asian (EAS)
AF:
AC:
0
AN:
39552
South Asian (SAS)
AF:
AC:
0
AN:
85836
European-Finnish (FIN)
AF:
AC:
0
AN:
53366
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
3
AN:
1110886
Other (OTH)
AF:
AC:
0
AN:
60304
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000096912), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.358
Heterozygous variant carriers
0
1
1
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2
3
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0.20
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
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8
10
<30
30-35
35-40
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (2)
1
-
-
Mucopolysaccharidosis, MPS-III-C (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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