chr8-43192397-A-AG

Variant names:

• chr8-43192397-A-AG
• rs483352894
• NM_152419.3:c.1345dupG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_152419.3(HGSNAT):​c.1345dupG​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. D449D) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.14
• Publications: 1 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):

• mucopolysaccharidosis type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• mucopolysaccharidosis type 3C

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics, G2P
• retinitis pigmentosa 73

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-43192397-A-AG is Pathogenic according to our data. Variant chr8-43192397-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 1231.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.1345dupG	p.Asp449GlyfsTer21	frameshift	Exon 13 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.1345dupG	p.Asp449GlyfsTer21	frameshift	Exon 13 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.1153dupG	p.Asp385GlyfsTer21	frameshift	Exon 11 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.1345dupG	p.Asp449GlyfsTer21	frameshift	Exon 13 of 18	ENSP00000368965.4
	HGSNAT	ENST00000902460.1		c.1345dupG	p.Asp449GlyfsTer21	frameshift	Exon 13 of 19	ENSP00000572519.1
	HGSNAT	ENST00000902456.1		c.1345dupG	p.Asp449GlyfsTer21	frameshift	Exon 13 of 19	ENSP00000572515.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248232 AF XY: 0.0000148

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461156 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 726824

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111688

Other (OTH) AF: 0.0000166 AC: 1 AN: 60350

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis, MPS-III-C (2)
1	-	-	Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (1)
1	-	-	Retinitis pigmentosa 73 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs483352894; hg19: chr8-43047540;