8-43172308-A-G

Position:

• chr8-43172308-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_152419.3(HGSNAT):​c.744-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HGSNAT NM_152419.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.48

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.8, offset of -38, new splice context is: agcccttccttttcacatAGcaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-43172308-A-G is Pathogenic according to our data. Variant chr8-43172308-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43172308-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGSNAT	NM_152419.3	c.744-2A>G		splice_acceptor_variant, intron_variant		ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGSNAT	ENST00000379644.9	c.744-2A>G		splice_acceptor_variant, intron_variant		2	NM_152419.3	ENSP00000368965.4
HGSNAT	ENST00000520704.1	n.*193-2A>G		splice_acceptor_variant, intron_variant		1		ENSP00000429109.1
HGSNAT	ENST00000522082.5	c.-18A>G		upstream_gene_variant		4		ENSP00000430151.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249250 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135220

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455678 Hom.: 0 Cov.: 28 AF XY: 0.00000414 AC XY: 3 AN XY: 724606

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The splice acceptor variant c.744-2A>G in HGSNAT (NM_152419.3) has previously been reported in homozygous state in the patient of Pakistani origin from the UK (Feldhammer et al, 2009 ). This variant has been reported to ClinVar as Likely Pathogenic. The c.744-2A>G variant is observed in 1/30,598 (0.0033%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant mutates a splice-acceptor sequence, potentially resulting in exon skipping and the production of abnormal proteins. The c.744-2A>G variant is a loss of function variant in the gene HGSNAT, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 17, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	30
DANN	Benign	0.95
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: -36
DS_AL_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs762402992; hg19: chr8-43027451;