Genetic Variant HGSNAT:p.Gly133Glu (chr8-43158949-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_152419.3(HGSNAT):c.398G>A(p.Gly133Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G133A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.22

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):

mucopolysaccharidosis type 3
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
mucopolysaccharidosis type 3C
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics, G2P
retinitis pigmentosa 73
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-43158949-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 208814.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3 link	c.398G>A	p.Gly133Glu	missense_variant	Exon 4 of 18	ENST00000379644.9	NP_689632.2	Q68CP4-2Q8IVU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HGSNAT	ENST00000379644.9 link	c.398G>A	p.Gly133Glu	missense_variant	Exon 4 of 18	2	NM_152419.3	ENSP00000368965.4	Q68CP4-2
HGSNAT	ENST00000520704.1 link	n.248G>A		non_coding_transcript_exon_variant	Exon 4 of 10	1		ENSP00000429109.1	E5RJC4
HGSNAT	ENST00000517319.1 link	n.261G>A		non_coding_transcript_exon_variant	Exon 3 of 5	4		ENSP00000430032.1	E5RH11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459056

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725764

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

85952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110128

Other (OTH)

AF:

0.00

AC:

AN:

60288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00109982), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.98

PhyloP100

5.2

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.85

MVP

0.93

MPC

0.59

ClinPred

0.99

GERP RS

6.0

gMVP

0.95

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over