Variant chr8-43192397-A-AG details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_152419.3(HGSNAT):c.1345dup(p.Asp449GlyfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000267 in 1,461,156 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: 0.000027 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.14

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

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 8-43192397-A-AG is Pathogenic according to our data. Variant chr8-43192397-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 1231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGSNAT	NM_152419.3 linkuse as main transcript	c.1345dup	p.Asp449GlyfsTer21	frameshift_variant	13/18	ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGSNAT	ENST00000379644.9 linkuse as main transcript	c.1345dup	p.Asp449GlyfsTer21	frameshift_variant	13/18	2	NM_152419.3	ENSP00000368965	P3	Q68CP4-2
HGSNAT	ENST00000521576.1 linkuse as main transcript	c.496dup	p.Asp166GlyfsTer21	frameshift_variant	4/9	2		ENSP00000429029	A2
HGSNAT	ENST00000524016.5 linkuse as main transcript	c.449dup	p.Asp151GlyfsTer21	frameshift_variant	4/7	4		ENSP00000428322
HGSNAT	ENST00000520678.1 linkuse as main transcript	n.278dup		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

248232

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134684

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461156

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726824

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 22, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

This sequence change creates a premature translational stop signal (p.Asp449Glyfs*21) 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). This variant is present in population databases (rs483352894, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type IIIC (PMID: 16960811, 19479962, 31228227). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1231). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 73

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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