rs121908282

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_152419.3(HGSNAT):​c.848C>A​(p.Pro283Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P283S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HGSNAT
NM_152419.3 missense

Scores

9
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.02
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]

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_152419.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-43173740-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HGSNATNM_152419.3 linkc.848C>A p.Pro283Gln missense_variant Exon 9 of 18 ENST00000379644.9 NP_689632.2 Q68CP4-2Q8IVU6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HGSNATENST00000379644.9 linkc.848C>A p.Pro283Gln missense_variant Exon 9 of 18 2 NM_152419.3 ENSP00000368965.4 Q68CP4-2
HGSNATENST00000520704.1 linkn.*297C>A non_coding_transcript_exon_variant Exon 10 of 10 1 ENSP00000429109.1 E5RJC4
HGSNATENST00000520704.1 linkn.*297C>A 3_prime_UTR_variant Exon 10 of 10 1 ENSP00000429109.1 E5RJC4
HGSNATENST00000522082.5 linkc.89C>A p.Pro30Gln missense_variant Exon 2 of 6 4 ENSP00000430151.1 E5RGH7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1460280
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726292
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33468
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44564
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26092
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39668
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
85896
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53308
Gnomad4 NFE exome
AF:
0.00
AC:
0
AN:
1111194
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
60326
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
27
DANN
Uncertain
0.99
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
1.1
D
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-7.2
D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Vest4
0.90
MVP
0.94
MPC
0.50
ClinPred
1.0
D
GERP RS
5.2
gMVP
0.92
Mutation Taster
=6/94
disease causing

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908282; hg19: chr8-43028883; COSMIC: COSV101108323; COSMIC: COSV101108323; API