chr8-43140481-C-CGAGCGGGCGGCGGGCAT

Position:

• chr8-43140481-C-CGAGCGGGCGGCGGGCAT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_152419.3(HGSNAT):​c.-8_9dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 148,138 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: HGSNAT NM_152419.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0590

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 Benign. Variant got -8 ACMG points.

• BP6: Variant 8-43140481-C-CGAGCGGGCGGCGGGCAT is Benign according to our data. Variant chr8-43140481-C-CGAGCGGGCGGCGGGCAT is described in ClinVar as [Likely_benign]. Clinvar id is 496551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGSNAT	NM_152419.3	c.-8_9dup		5_prime_UTR_variant	1/18	ENST00000379644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGSNAT	ENST00000379644.9	c.-8_9dup		5_prime_UTR_variant	1/18	2	NM_152419.3	P3
HGSNAT	ENST00000520704.1			upstream_gene_variant		1
HGSNAT	ENST00000517319.1			upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 252 AN: 148032 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000634

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000807

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.00197

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00284 AC: 2388 AN: 841436 Hom.: 2 Cov.: 17 AF XY: 0.00292 AC XY: 1144 AN XY: 391332

Gnomad4 AFR exome AF: 0.000251

Gnomad4 AMR exome AF: 0.000601

Gnomad4 ASJ exome AF: 0.000361

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000427

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00125

GnomAD4 genome AF: 0.00170 AC: 252 AN: 148138 Hom.: 1 Cov.: 32 AF XY: 0.00143 AC XY: 103 AN XY: 72186

Gnomad4 AFR AF: 0.000632

Gnomad4 AMR AF: 0.000805

Gnomad4 ASJ AF: 0.00118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000221

Gnomad4 NFE AF: 0.00304

Gnomad4 OTH AF: 0.00195

Alfa AF: 0.00184 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 20, 2019

Variant summary: HGSNAT c.-8_9dup17 causes a duplication of nucleotides spanning the 5' UTR and the first 3 amino acids of the gene that would result in the generation of a nearby downstream alternative translation initiation codon (together with its consensus Kozak sequence). 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 26166 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.002 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HGSNAT causing Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.-8_9dup17 in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) and no experimental evidence demonstrating its impact on protein function have been reported. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

HGSNAT: BP4 -

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: rs1215061130; hg19: chr8-42995624;