8-43140525-C-CGCTGCTGCTGGCCGCGTCCGT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_152419.3(HGSNAT):​c.34_54dup​(p.Leu12_Leu18dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,103,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A10A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.718
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]

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;
PM4
Nonframeshift variant in NON repetitive region in NM_152419.3.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HGSNATNM_152419.3 linkuse as main transcriptc.34_54dup p.Leu12_Leu18dup inframe_insertion 1/18 ENST00000379644.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HGSNATENST00000379644.9 linkuse as main transcriptc.34_54dup p.Leu12_Leu18dup inframe_insertion 1/182 NM_152419.3 P3Q68CP4-2
HGSNATENST00000520704.1 linkuse as main transcriptc.-117_-97dup 5_prime_UTR_variant, NMD_transcript_variant 1/101
HGSNATENST00000517319.1 linkuse as main transcriptc.34_54dup p.Leu12_Leu18dup inframe_insertion, NMD_transcript_variant 1/54

Frequencies

GnomAD3 genomes
AF:
0.000108
AC:
16
AN:
148468
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000244
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000134
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:
0.000195
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000142
AC:
136
AN:
955390
Hom.:
0
Cov.:
29
AF XY:
0.000149
AC XY:
67
AN XY:
450448
show subpopulations
Gnomad4 AFR exome
AF:
0.0000534
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000157
Gnomad4 OTH exome
AF:
0.0000864
GnomAD4 genome
AF:
0.000108
AC:
16
AN:
148576
Hom.:
0
Cov.:
32
AF XY:
0.000124
AC XY:
9
AN XY:
72470
show subpopulations
Gnomad4 AFR
AF:
0.0000243
Gnomad4 AMR
AF:
0.000134
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000195
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000843
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jan 17, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylJan 05, 2017- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 14, 2018Variant summary: HGSNAT c.34_54dup21 (p.Leu12_Leu18dup) results in an in-frame insertion that is predicted to insert 7 amino acids into the encoded protein. The variant allele was found at a frequency of 7.5e-05 in 26610 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HGSNAT causing Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (7.5e-05 vs 0.001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.34_54dup21 in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 09, 2022This variant, c.34_54dup, results in the insertion of 7 amino acid(s) of the HGSNAT protein (p.Leu12_Leu18dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with HGSNAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 550260). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs961025173; hg19: chr8-42995668; API