rs112029032

Variant names:

• chr8-43199504-G-A
• rs112029032
• NM_152419.3:c.1843G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:5 B:11
• Conservation: PhyloP100: 7.64

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 -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	c.1843G>A	p.Ala615Thr	missense_variant	Exon 18 of 18	ENST00000379644.9	NP_689632.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 538 AN: 152138 Hom.: 2 Cov.: 33

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.: 4 AF XY: 0.00393 AC XY: 524 AN XY: 133334

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.: 21 Cov.: 32 AF XY: 0.00491 AC XY: 3561 AN XY: 724910

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.: 2 Cov.: 33 AF XY: 0.00341 AC XY: 254 AN XY: 74440

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.: 1

Bravo AF: 0.00329

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00414 AC: 503

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00559

EpiControl AF: 0.00601

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Oct 09, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27608171, 25859010, 20583299, 19479962, 19823584, 17033958, 28041643, 29144512, 28981474, 31456290, 32770643, 32581362, 33576794) -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HGSNAT: BS2 -

Mar 01, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Retinitis pigmentosa 73 Pathogenic:3 Uncertain:2

Jan 31, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PM3_STR -

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 17, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mucopolysaccharidosis, MPS-III-C Pathogenic:1 Benign:3

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 22, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2 Uncertain:1

May 13, 2020

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Benign:3

Jun 25, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2023

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.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. -

Retinitis pigmentosa Pathogenic:2

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

Apr 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.60	T
PrimateAI	Uncertain	0.59	T
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	T
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

Other links and lift over

dbSNP: rs112029032; hg19: chr8-43054647; COSMIC: COSV52818611; COSMIC: COSV52818611;