chr8-43197919-G-C

Position:

chr8-43197919-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_152419.3(HGSNAT):c.1693G>C(p.Gly565Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,782 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 91 hom. )

Consequence

HGSNAT
NM_152419.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.38

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077331364).

BP6

Variant 8-43197919-G-C is Benign according to our data. Variant chr8-43197919-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 363152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43197919-G-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGSNAT	NM_152419.3 linkuse as main transcript	c.1693G>C	p.Gly565Arg	missense_variant	17/18	ENST00000379644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGSNAT	ENST00000379644.9 linkuse as main transcript	c.1693G>C	p.Gly565Arg	missense_variant	17/18	2	NM_152419.3	P3	Q68CP4-2
HGSNAT	ENST00000519705.1 linkuse as main transcript	n.1009G>C		non_coding_transcript_exon_variant	3/4	1
HGSNAT	ENST00000521576.1 linkuse as main transcript	c.844G>C	p.Gly282Arg	missense_variant	8/9	2		A2
HGSNAT	ENST00000523989.1 linkuse as main transcript			downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00630

AC:

959

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00666

AC:

1659

AN:

249042

Hom.:

AF XY:

0.00707

AC XY:

955

AN XY:

135106

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00313

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00825

Gnomad FIN exome

AF:

0.00478

Gnomad NFE exome

AF:

0.00992

Gnomad OTH exome

AF:

0.00563

GnomAD4 exome

AF:

0.0111

AC:

16244

AN:

1461480

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

7891

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.00302

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00764

Gnomad4 FIN exome

AF:

0.00476

Gnomad4 NFE exome

AF:

0.0131

Gnomad4 OTH exome

AF:

0.00906

GnomAD4 genome

AF:

0.00630

AC:

959

AN:

152302

Hom.:

Cov.:

AF XY:

0.00624

AC XY:

465

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00257

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00725

Gnomad4 FIN

AF:

0.00377

Gnomad4 NFE

AF:

0.0105

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00852

Hom.:

Bravo

AF:

0.00619

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00181

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00633

AC:

765

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	HGSNAT: BP4, BS1, BS2 -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 28, 2022	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.86

Eigen

Benign

-0.21

Eigen_PC

Benign

0.00046

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-0.63

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.90

N;N

REVEL

Benign

0.24

Sift

Benign

0.72

T;T

Sift4G

Benign

0.85

T;T

Vest4

0.28

MVP

0.86

MPC

0.12

ClinPred

0.0078

GERP RS

5.1

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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