rs112029032

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_152419.3(HGSNAT):c.1843G>A(p.Ala615Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,610,166 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 21 hom. )

Consequence

HGSNAT
NM_152419.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:5B:11

Conservation

PhyloP100: 7.64

Variant links:

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]

HGSNAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011618704).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00353 (538/152256) while in subpopulation NFE AF= 0.00559 (380/68026). AF 95% confidence interval is 0.00512. There are 2 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3 link	c.1843G>A	p.Ala615Thr	missense_variant	Exon 18 of 18	ENST00000379644.9	NP_689632.2	Q68CP4-2Q8IVU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HGSNAT	ENST00000379644.9 link	c.1843G>A	p.Ala615Thr	missense_variant	Exon 18 of 18	2	NM_152419.3	ENSP00000368965.4	Q68CP4-2
HGSNAT	ENST00000519705.1 link	n.1159G>A		non_coding_transcript_exon_variant	Exon 4 of 4	1
HGSNAT	ENST00000521576.1 link	c.994G>A	p.Ala332Thr	missense_variant	Exon 9 of 9	2		ENSP00000429029.1	E5RJN0

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

538

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00406

AC:

999

AN:

246284

Hom.:

AF XY:

0.00393

AC XY:

524

AN XY:

133334

show subpopulations

Gnomad AFR exome

AF:

0.000830

Gnomad AMR exome

AF:

0.000891

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.00303

Gnomad FIN exome

AF:

0.00439

Gnomad NFE exome

AF:

0.00535

Gnomad OTH exome

AF:

0.00385

GnomAD4 exome

AF:

0.00512

AC:

7460

AN:

1457910

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

3561

AN XY:

724910

show subpopulations

Gnomad4 AFR exome

AF:

0.000779

Gnomad4 AMR exome

AF:

0.000997

Gnomad4 ASJ exome

AF:

0.0138

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.00279

Gnomad4 FIN exome

AF:

0.00538

Gnomad4 NFE exome

AF:

0.00564

Gnomad4 OTH exome

AF:

0.00403

GnomAD4 genome

AF:

0.00353

AC:

538

AN:

152256

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

254

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.00559

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.00329

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00414

AC:

503

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00559

EpiControl

AF:

0.00601

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:5Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	HGSNAT: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 01, 2023	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 09, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The HGSNAT p.Ala615Thr variant was identified in 2 of 83 families with Mucopolysaccharidosis Type III (freq: 0.012), and was found as a complex allele with the HGSNAT p.W403C variant (Feldhammer_2009_PMID:19479962). Functional studies demonstrate that the p.A615T variant on its own does not affect HGSNAT protein function, however when found with the p.W403C variant there was a loss of HGSNAT protein activity (Feldhammer_2009_PMID:19479962; Fedele_2010_PMID:20583299). The p.A615T variant was also found as a homozygous variant in three affected members of a Dutch family with non-syndromic retinitis pigmentosa; all three affected family members were also heterozygous for another variant in the HGSNAT gene (p.G133A) (Haer-Wigman_2015_PMID:25859010). In a cohort of 722 individuals with inherited retinal disease, the p.A615T variant was identified in two patients with retinal dystrophy (freq: 0.001) (Carss_2017_PMID:28041643). The variant was identified in the following databases: dbSNP (ID: rs112029032), LOVD 3.0 and ClinVar (classified as benign by EGL Genetic Diagnostics, as likely benign by ARUP laboratories and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen and as likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 1119 of 277692 chromosomes (4 homozygous) at a frequency of 0.00403 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 148 of 10188 chromosomes (freq: 0.01453), European (non-Finnish) in 691 of 127570 chromosomes (freq: 0.005417), European (Finnish) in 106 of 24896 chromosomes (freq: 0.004258), Other in 28 of 7056 chromosomes (freq: 0.003968), South Asian in 90 of 29666 chromosomes (freq: 0.003034), African in 23 of 24384 chromosomes (freq: 0.000943), Latino in 31 of 34504 chromosomes (freq: 0.000898), and East Asian in 2 of 19428 chromosomes (freq: 0.000103). The p.Ala615 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2019	This variant is associated with the following publications: (PMID: 27608171, 25859010, 20583299, 19479962, 19823584, 17033958, 28041643, 29144512, 28981474, 31456290, 32770643, 32581362, 33576794) -

Retinitis pigmentosa 73

Pathogenic:3Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 31, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 24, 2024	Criteria applied: PS3,PM3_STR -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 17, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4. -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Mucopolysaccharidosis, MPS-III-C

Pathogenic:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 22, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Retinal dystrophy

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 13, 2020	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2023	Variant summary: HGSNAT c.1843G>A (p.Ala615Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 246284 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 4 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 benign. Experimental evidence evaluating an impact on protein function has been reported for this variant, with the most pronounced variant effect resulting in >50%-90% of normal activity in cultured fibroblasts and COS-7 cells (Feldhammer_2009) and HEK293T cells (Fedele_2010). Eighteen ClinVar submitters have assessed the variant since 2014: three classified the variant as pathogenic, three as likely pathogenic, four as uncertain significance, four as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jun 25, 2020	- -

Retinitis pigmentosa

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Ala615Thr variant in HGSNAT was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

HGSNAT-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2024

The HGSNAT c.1843G>A variant is predicted to result in the amino acid substitution p.Ala615Thr. This variant has been reported in the homozygous and compound heterozygous state in individuals with non-syndromic retinitis pigmentosa (Schiff et al 2020. PubMed ID: 32770643; Sharon et al. 2019. PubMed ID: 31456290 Table S2; Colombo et. al. 2021. PubMed ID: 33576794, Patel et al. 2021. PubMed ID: 34326763; Carrera et al. 2021. PubMed ID: 34580245; Carss et al. 2017. PubMed ID: 28041643 Table S2; Thorsteinsson et al. 2021. PubMed ID: 33851411; Internal Data, PreventionGenetics). This variant was also observed in cis with a second HGSNAT variant (p.Trp403Cys) in the homozygous state in patients with mucopolysaccharidosis IIIC (MPSIIIC) (Hrebicek et al. 2006. PubMed ID: 17033958, reported as p.[W431C;A643T]; Feldhammer et al. 2009. PubMed ID: 19823584). Functional studies have been inconclusive. The p.Ala615Thr variant alone resulted in a mild decrease in enzymatic function (Feldhammer et al. 2009, PubMed ID: 19823584; Fedele et al. 2010. PubMed ID: 20583299). However, one study showed that the haplotype with p.Ala615Thr and p.Trp403Cys on the same allele were additive, abolishing HGSNAT activity (Fedele et al. 2010. PubMed ID: 20583299). Patients with retinitis pigmentosa have reduced HGSNAT enzyme activity levels in blood leukocytes compared with healthy controls but higher than those in MPS IIIC patients (Haer-Wigman et al. 2015. PubMed ID: 25859010; Schiff et al 2020. PubMed ID: 32770643). Incomplete penetrance for retinitis pigmentosa has been reported for this variant when in the homozygous state (Schiff et al 2020. PubMed ID: 32770643). This variant is reported in 1.5% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including several homozygotes in multiple population groups. In summary, we conclude that this is likely a hypomorphic variant (partial loss-of-function) and is interpreted as likely pathogenic for non-syndromic retinitis pigmentosa. The clinical significance of this variant is currently uncertain for mucopolysaccharidosis type IIIC. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2025

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 615 of the HGSNAT protein (p.Ala615Thr). This variant is present in population databases (rs112029032, gnomAD 1.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with mucopolysaccharidosis IIIC as well as retinal dystrophy. This variant may be associated with a milder and/or later onset form of retinitis pigmentosa (PMID: 17033958, 19479962, 19823584, 20583299, 25859010, 27608171, 28981474, 31228227, 32770643, 33576794, 34795310). This variant is also known as A643T. ClinVar contains an entry for this variant (Variation ID: 208816). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HGSNAT protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HGSNAT function (PMID: 19479962, 19823584, 20583299). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.60

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.9

N;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.28

T;T

Vest4

0.50

MVP

0.82

MPC

0.11

ClinPred

0.043

GERP RS

5.3

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over