rs1064795522

Variant names:

• chr8-43192320-G-T
• rs1064795522
• NM_152419.3:c.1267G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-43192320-G-T
• chr8-43192320-G-A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PP3_Strong PP5

The NM_152419.3(HGSNAT):​c.1267G>T​(p.Gly423Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,084 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000571415: Published functional studies demonstrate a damaging effect on protein maturation, enzymatic activity, and lysosomal targeting/processing (Martins et al., 2019)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G423G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.21
• Publications: 3 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):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mucopolysaccharidosis type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• mucopolysaccharidosis type 3C

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 73

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000571415: Published functional studies demonstrate a damaging effect on protein maturation, enzymatic activity, and lysosomal targeting/processing (Martins et al., 2019); SCV002272474: Experimental studies have shown that this missense change affects HGSNAT function (PMID: 31228227).; SCV000699949: The variant shows negligible enzyme activity (Martins_2010).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_152419.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 8-43192320-G-T is Pathogenic according to our data. Variant chr8-43192320-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422050.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152419.3. 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.1267G>T	p.Gly423Trp	missense	Exon 13 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.1267G>T	p.Gly423Trp	missense	Exon 13 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.1075G>T	p.Gly359Trp	missense	Exon 11 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.1267G>T	p.Gly423Trp	missense	Exon 13 of 18	ENSP00000368965.4	Q68CP4-2
	HGSNAT	ENST00000902460.1		c.1267G>T	p.Gly423Trp	missense	Exon 13 of 19	ENSP00000572519.1
	HGSNAT	ENST00000902456.1		c.1267G>T	p.Gly423Trp	missense	Exon 13 of 19	ENSP00000572515.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456084 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723760

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 43818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5184

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109710

Other (OTH) AF: 0.00 AC: 0 AN: 60158

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Mucopolysaccharidosis, MPS-III-C (1)
1	-	-	Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (1)
1	-	-	not provided (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Sanfilippo syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.22	D
PhyloP100		9.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.92
MVP		0.90
MPC		0.56
ClinPred		1.0	D
GERP RS		5.0
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064795522; hg19: chr8-43047463;