rs121908284

Positions:

chr8-43193824-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_152419.3(HGSNAT):c.1445T>A(p.Met482Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.82

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a topological_domain Lumenal, vesicle (size 58) in uniprot entity HGNAT_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_152419.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

PP5

Variant 8-43193824-T-A is Pathogenic according to our data. Variant chr8-43193824-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43193824-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGSNAT	NM_152419.3 linkuse as main transcript	c.1445T>A	p.Met482Lys	missense_variant	14/18	ENST00000379644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGSNAT	ENST00000379644.9 linkuse as main transcript	c.1445T>A	p.Met482Lys	missense_variant	14/18	2	NM_152419.3	P3	Q68CP4-2
HGSNAT	ENST00000521576.1 linkuse as main transcript	c.596T>A	p.Met199Lys	missense_variant	5/9	2		A2
HGSNAT	ENST00000524016.5 linkuse as main transcript	c.551T>A	p.Met184Lys	missense_variant	5/7	4
HGSNAT	ENST00000520678.1 linkuse as main transcript	n.378T>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 482 of the HGSNAT protein (p.Met482Lys). This variant is present in population databases (rs121908284, gnomAD 0.007%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIC (PMID: 17033958). This variant is also known as c.1529T>A, p.M510K. ClinVar contains an entry for this variant (Variation ID: 1234). 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) has been performed at Invitae 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 have shown that this missense change affects HGSNAT function (PMID: 19823584, 20583299). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Sanfilippo syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 12, 2023

Variant summary: HGSNAT c.1445T>A (p.Met482Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249234 control chromosomes (gnomAD). c.1445T>A has been reported in the literature in an individual affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (example: Hrebicek_HGSNAT_2006). Multiple publications have reported this variant impairs normal protein activity (examples: Feldhammer_2009 and Fedele_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20583299, 19823584, 17033958). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Benign

0.96

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.20

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0080

D;D

Vest4

0.94

MVP

0.86

MPC

0.25

ClinPred

0.98

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.98

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