rs727503962

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_152419.3(HGSNAT):c.710C>A(p.Pro237Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000311 in 1,607,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.158

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a mutagenesis_site Displayed both lysosomal and plasma membrane localization, reduced intralysosomal proteolytic cleavage and enzymatic activity; when associated with A-208. (size 0) in uniprot entity HGNAT_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGSNAT	NM_152419.3 link	c.710C>A	p.Pro237Gln	missense_variant	7/18	ENST00000379644.9	NP_689632.2	Q68CP4-2Q8IVU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HGSNAT	ENST00000379644.9 link	c.710C>A	p.Pro237Gln	missense_variant	7/18	2	NM_152419.3	ENSP00000368965.4	Q68CP4-2
HGSNAT	ENST00000520704.1 link	n.*159C>A		non_coding_transcript_exon_variant	8/10	1		ENSP00000429109.1	E5RJC4
HGSNAT	ENST00000520704.1 link	n.*159C>A		3_prime_UTR_variant	8/10	1		ENSP00000429109.1	E5RJC4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000296

AC:

AN:

236610

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

128096

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000316

AC:

AN:

1455180

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

723176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000307

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 20, 2017	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 22, 2021	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 237 of the HGSNAT protein (p.Pro237Gln). This variant is present in population databases (rs727503962, gnomAD 0.01%). This missense change has been observed in individual(s) with Sanfillipo syndrome (PMID: 17033958, 18024218, 33673364; Invitae). ClinVar contains an entry for this variant (Variation ID: 167177). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HGSNAT protein function. Experimental studies have shown that this missense change does not substantially affect HGSNAT function (PMID: 19823584, 20583299, 20825431). 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

6.8

DANN

Benign

0.74

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.59

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.63

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.58

Sift

Benign

0.22

Sift4G

Benign

0.34

Vest4

0.74

MVP

0.72

MPC

0.099

ClinPred

0.018

GERP RS

-0.51

gMVP

0.35

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