rs747240928

Variant names:

• chr8-43196999-C-G
• rs747240928
• NM_152419.3:c.1516C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-43196999-C-G
• chr8-43196999-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001363227.2(HGSNAT):​c.1603C>G​(p.Arg535Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R535Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HGSNAT NM_001363227.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.187
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363227.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGSNAT	NM_152419.3	MANE Select	c.1516C>G	p.Arg506Gly	missense	Exon 15 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.1603C>G	p.Arg535Gly	missense	Exon 16 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.1324C>G	p.Arg442Gly	missense	Exon 13 of 16	NP_001350157.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGSNAT	ENST00000379644.9	TSL:2 MANE Select	c.1516C>G	p.Arg506Gly	missense	Exon 15 of 18	ENSP00000368965.4
	HGSNAT	ENST00000519705.1	TSL:1	n.832C>G		non_coding_transcript_exon	Exon 1 of 4
	HGSNAT	ENST00000902460.1		c.1717C>G	p.Arg573Gly	missense	Exon 16 of 19	ENSP00000572519.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459246 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726098

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109792

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.029	D
PhyloP100		0.19
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Vest4		0.90
MVP		0.78
MPC		0.59
ClinPred		1.0	D
GERP RS		-0.43
gMVP		0.85
Mutation Taster		=31/69	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

Other links and lift over

dbSNP: rs747240928; hg19: chr8-43052142;