8-43140525-CGCTGCTGCTGGCCGCGTCCGT-CGCTGCTGCTGGCCGCGTCCGTGCTGCTGCTGGCCGCGTCCGT

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_152419.3(HGSNAT):c.34_54dupCTGCTGGCCGCGTCCGTGCTG(p.Leu12_Leu18dup) variant causes a conservative 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S19S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.718

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: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_152419.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3 link	c.34_54dupCTGCTGGCCGCGTCCGTGCTG	p.Leu12_Leu18dup	conservative_inframe_insertion	Exon 1 of 18	ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HGSNAT	ENST00000379644.9 link	c.34_54dupCTGCTGGCCGCGTCCGTGCTG	p.Leu12_Leu18dup	conservative_inframe_insertion	Exon 1 of 18	2	NM_152419.3	ENSP00000368965.4
HGSNAT	ENST00000520704.1 link	n.-117_-97dupCTGCTGGCCGCGTCCGTGCTG		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000429109.1
HGSNAT	ENST00000520704.1 link	n.-117_-97dupCTGCTGGCCGCGTCCGTGCTG		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000429109.1
HGSNAT	ENST00000517319.1 link	n.34_54dupCTGCTGGCCGCGTCCGTGCTG		non_coding_transcript_exon_variant	Exon 1 of 5	4		ENSP00000430032.1

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

148468

Hom.:

Cov.:

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.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

450448

show subpopulations

African (AFR)

AF:

0.0000534

AC:

AN:

18728

American (AMR)

AF:

0.00

AC:

AN:

4364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9054

East Asian (EAS)

AF:

0.00

AC:

AN:

13822

South Asian (SAS)

AF:

0.00

AC:

AN:

18832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2244

European-Non Finnish (NFE)

AF:

0.000157

AC:

132

AN:

841914

Other (OTH)

AF:

0.0000864

AC:

AN:

34726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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

AF:

0.000108

AC:

AN:

148576

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

72470

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41162

American (AMR)

AF:

0.000134

AC:

AN:

14950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000195

AC:

AN:

66640

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000843

Hom.:

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

Jan 17, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified

Uncertain:1

May 14, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant 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

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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

PhyloP100

0.72

Mutation Taster

=75/25

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over