rs112029032

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PS3 BP4_Strong BS1 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). ClinVar reports functional evidence for this variant: "SCV004112609: 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" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A615A) has been classified as Likely benign.

• 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:10 U:7 B:9 O:1
• Conservation: PhyloP100: 7.64
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mucopolysaccharidosis type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• mucopolysaccharidosis type 3C

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 73

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004112609: 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).
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152419.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGSNAT	NM_152419.3	MANE Select	c.1843G>A	p.Ala615Thr	missense	Exon 18 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.1930G>A	p.Ala644Thr	missense	Exon 19 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.1651G>A	p.Ala551Thr	missense	Exon 16 of 16	NP_001350157.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGSNAT	ENST00000379644.9	TSL:2 MANE Select	c.1843G>A	p.Ala615Thr	missense	Exon 18 of 18	ENSP00000368965.4	Q68CP4-2
	HGSNAT	ENST00000519705.1	TSL:1	n.1159G>A		non_coding_transcript_exon	Exon 4 of 4
	HGSNAT	ENST00000902460.1		c.2044G>A	p.Ala682Thr	missense	Exon 19 of 19	ENSP00000572519.1

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

GnomAD2 exomes AF: 0.00406 AC: 999 AN: 246284 AF XY: 0.00393

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 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

African (AFR) AF: 0.000779 AC: 26 AN: 33378

American (AMR) AF: 0.000997 AC: 44 AN: 44146

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 358 AN: 25982

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39598

South Asian (SAS) AF: 0.00279 AC: 238 AN: 85348

European-Finnish (FIN) AF: 0.00538 AC: 287 AN: 53314

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00564 AC: 6260 AN: 1110160

Other (OTH) AF: 0.00403 AC: 243 AN: 60230

GnomAD4 genome AF: 0.00353 AC: 538 AN: 152256 Hom.: 2 Cov.: 33 AF XY: 0.00341 AC XY: 254 AN XY: 74440

African (AFR) AF: 0.00116 AC: 48 AN: 41542

American (AMR) AF: 0.00111 AC: 17 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00559 AC: 380 AN: 68026

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00380 Hom.: 7

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	4	not provided (6)
3	2	-	Retinitis pigmentosa 73 (6)
1	-	3	Mucopolysaccharidosis, MPS-III-C (4)
-	1	2	not specified (3)
2	1	-	Retinal dystrophy (3)
2	-	-	Retinitis pigmentosa (2)
1	-	-	HGSNAT-related disorder (1)
-	1	-	Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (1)
-	1	-	Retinal disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
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
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.60	T
PhyloP100		7.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.28	T
Vest4		0.50
MVP		0.82
MPC		0.11
ClinPred		0.043	T
GERP RS		5.3
gMVP		0.68
Mutation Taster		=38/62	disease causing (ClinVar)

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

Other links and lift over

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