chr8-43140481-C-CGAGCGGGCGGCGGGCAT

Variant names:

• chr8-43140481-C-CGAGCGGGCGGCGGGCAT
• rs1215061130
• NM_152419.3:c.-8_9dupCGGCGGGCATGAGCGGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 8P and 12B. PVS1 BP6_Very_Strong BS1

The NM_152419.3(HGSNAT):​c.-8_9dupCGGCGGGCATGAGCGGG​(p.Ala4fs) variant causes a frameshift, stop gained 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified 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 frameshift, stop_gained
• 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

Our verdict: Likely_benign. The variant received -4 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 177 pathogenic variants in the truncated region.
• 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.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0017 (252/148138) while in subpopulation NFE AF = 0.00304 (202/66458). AF 95% confidence interval is 0.0027. There are 1 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3	c.-8_9dupCGGCGGGCATGAGCGGG	p.Ala4fs	frameshift_variant, stop_gained	Exon 1 of 18	ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGSNAT	ENST00000379644.9	c.-8_9dupCGGCGGGCATGAGCGGG	p.Ala4fs	frameshift_variant, stop_gained	Exon 1 of 18	2	NM_152419.3	ENSP00000368965.4

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 AC: 4 AN: 15954

Gnomad4 AMR exome AF: 0.000601 AC: 1 AN: 1664

Gnomad4 ASJ exome AF: 0.000361 AC: 2 AN: 5544

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 4260

Gnomad4 SAS exome AF: 0.000116 AC: 2 AN: 17182

Gnomad4 FIN exome AF: 0.000427 AC: 1 AN: 2342

Gnomad4 NFE exome AF: 0.00306 AC: 2340 AN: 764706

Gnomad4 Remaining exome AF: 0.00125 AC: 35 AN: 28090

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 AC: 0.00063248 AN: 0.00063248

Gnomad4 AMR AF: 0.000805 AC: 0.000805477 AN: 0.000805477

Gnomad4 ASJ AF: 0.00118 AC: 0.00117578 AN: 0.00117578

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000414 AC: 0.000414079 AN: 0.000414079

Gnomad4 FIN AF: 0.000221 AC: 0.000220507 AN: 0.000220507

Gnomad4 NFE AF: 0.00304 AC: 0.00303951 AN: 0.00303951

Gnomad4 OTH AF: 0.00195 AC: 0.00194553 AN: 0.00194553

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

Feb 20, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 07, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HGSNAT: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=34/166	disease causing (fs/PTC)

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;