rs73675469

Positions:

• chr8-43199501-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152419.3(HGSNAT):​c.1840G>A​(p.Val614Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,611,490 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V614V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (132 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (159 hom.)
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.186

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001986146).
• BP6: Variant 8-43199501-G-A is Benign according to our data. Variant chr8-43199501-G-A is described in ClinVar as [Benign]. Clinvar id is 167178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGSNAT	NM_152419.3	c.1840G>A	p.Val614Ile	missense_variant	18/18	ENST00000379644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGSNAT	ENST00000379644.9	c.1840G>A	p.Val614Ile	missense_variant	18/18	2	NM_152419.3	P3
HGSNAT	ENST00000519705.1	n.1156G>A		non_coding_transcript_exon_variant	4/4	1
HGSNAT	ENST00000521576.1	c.991G>A	p.Val331Ile	missense_variant	9/9	2		A2

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3535 AN: 152086 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.0795

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.00704 AC: 1741 AN: 247236 Hom.: 61 AF XY: 0.00619 AC XY: 828 AN XY: 133846

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00300

GnomAD4 exome AF: 0.00305 AC: 4445 AN: 1459286 Hom.: 159 Cov.: 32 AF XY: 0.00293 AC XY: 2129 AN XY: 725686

Gnomad4 AFR exome AF: 0.0865

Gnomad4 AMR exome AF: 0.00473

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00978

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.0233 AC: 3548 AN: 152204 Hom.: 132 Cov.: 32 AF XY: 0.0233 AC XY: 1737 AN XY: 74422

Gnomad4 AFR AF: 0.0797

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00409 Hom.: 43

Bravo AF: 0.0266

ESP6500AA AF: 0.0734 AC: 323

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00841 AC: 1021

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000357

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 23, 2013

- -

Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.9
DANN	Benign	0.34
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.059
Sift	Benign	0.82	T;T
Sift4G	Benign	0.95	T;T
Vest4		0.053
MVP		0.14
MPC		0.083
ClinPred		0.0017	T
GERP RS		2.5
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs73675469; hg19: chr8-43054644; COSMIC: COSV52817864; COSMIC: COSV52817864;