8-43140504-G-GGC

Position:

• chr8-43140504-G-GGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152419.3(HGSNAT):​c.9_10insCG​(p.Ala4fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGSNAT NM_152419.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0990

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 78 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-43140504-G-GGC is Pathogenic according to our data. Variant chr8-43140504-G-GGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558679.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGSNAT	NM_152419.3	c.9_10insCG	p.Ala4fs	frameshift_variant	1/18	ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGSNAT	ENST00000379644.9	c.9_10insCG	p.Ala4fs	frameshift_variant	1/18	2	NM_152419.3	ENSP00000368965.4
HGSNAT	ENST00000520704.1	n.-142_-141insCG		non_coding_transcript_exon_variant	1/10	1		ENSP00000429109.1
HGSNAT	ENST00000520704.1	n.-142_-141insCG		5_prime_UTR_variant	1/10	1		ENSP00000429109.1
HGSNAT	ENST00000517319.1	n.9_10insCG		non_coding_transcript_exon_variant	1/5	4		ENSP00000430032.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 06, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554526454; hg19: chr8-42995647;