rs754875934

Positions:

chr8-43158710-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_152419.3(HGSNAT):c.370A>T(p.Arg124Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,600,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 missense, splice_region

Scores

Splicing: ADA: 0.9910

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 3.02

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 8-43158710-A-T is Pathogenic according to our data. Variant chr8-43158710-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208815.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr8-43158710-A-T 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.370A>T	p.Arg124Trp	missense_variant, splice_region_variant	3/18	ENST00000379644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGSNAT	ENST00000379644.9 linkuse as main transcript	c.370A>T	p.Arg124Trp	missense_variant, splice_region_variant	3/18	2	NM_152419.3	P3	Q68CP4-2
HGSNAT	ENST00000520704.1 linkuse as main transcript	c.220A>T	p.Arg74Trp	missense_variant, splice_region_variant, NMD_transcript_variant	3/10	1
HGSNAT	ENST00000517319.1 linkuse as main transcript	c.235-213A>T		intron_variant, NMD_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000208

AC:

AN:

240818

Hom.:

AF XY:

0.0000306

AC XY:

AN XY:

130602

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000212

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000272

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1448212

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

718558

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000195

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000181

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinitis pigmentosa 73

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 29, 2022	This variant was identified as compound heterozygous with NM_152419.3:c.1843G>A._x000D_ Criteria applied: PS3, PM3_STR, PM2_SUP -

Mucopolysaccharidosis, MPS-III-C

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2021	NM_152419.2(HGSNAT):c.370A>T(R124W) is a missense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIC. R124W has not been observed in cases with relevant disease. Functional assessments of this variant are available in the literature (PMID: 25859010). R124W has been observed in population frequency databases (gnomAD ASJ 0.02%). In summary, there is insufficient evidence to classify NM_152419.2(HGSNAT):c.370A>T(R124W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 124 of the HGSNAT protein (p.Arg124Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs754875934, gnomAD 0.02%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 25859010; Invitae). ClinVar contains an entry for this variant (Variation ID: 208815). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in partial skipping of exon 3 and introduces a premature termination codon (PMID: 25859010). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2022

Missense variant demonstrated to result in partial exon skipping in a gene for which loss-of-function is a known mechanism of disease (Haer-Wigman et al., 2015); This variant is associated with the following publications: (PMID: 25859010, 31456290, 32770643, 34426522) -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 18, 2019

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Benign

0.16

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

0.53

MutationTaster

Benign

0.77

N;N

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.011

Vest4

0.70

MVP

0.91

MPC

0.51

ClinPred

0.84

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: -7

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