dbSNP rs370717845: HGSNAT:p.Gly173Asp (chr8-43161462-G-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_152419.3(HGSNAT):c.518G>A(p.Gly173Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G173S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

HGSNAT
NM_152419.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 2.09

Publications

0 publications found

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

HGSNAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.814

PP5

Variant 8-43161462-G-A is Pathogenic according to our data. Variant chr8-43161462-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 252961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HGSNAT	NM_152419.3	MANE Select	c.518G>A	p.Gly173Asp	missense	Exon 5 of 18	NP_689632.2
HGSNAT	NM_001363227.2		c.518G>A	p.Gly173Asp	missense	Exon 5 of 19	NP_001350156.1
HGSNAT	NM_001363228.2		c.518G>A	p.Gly173Asp	missense	Exon 5 of 16	NP_001350157.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HGSNAT	ENST00000379644.9	TSL:2 MANE Select	c.518G>A	p.Gly173Asp	missense	Exon 5 of 18	ENSP00000368965.4
HGSNAT	ENST00000520704.1	TSL:1	n.368G>A		non_coding_transcript_exon	Exon 5 of 10	ENSP00000429109.1
HGSNAT	ENST00000902460.1		c.518G>A	p.Gly173Asp	missense	Exon 5 of 19	ENSP00000572519.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis, MPS-III-C (3)

Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (1)

not provided (1)

Sanfilippo syndrome (1)

Mucopolysaccharidosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.017

Eigen_PC

Benign

0.023

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.75

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.33

PhyloP100

2.1

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.49

Sift

Benign

0.040

Sift4G

Benign

0.21

Vest4

0.89

MVP

0.91

MPC

0.32

ClinPred

0.68

GERP RS

4.5

gMVP

0.87

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over