rs148632988

Variant names:

• chr8-43197919-G-C
• rs148632988
• NM_152419.3:c.1693G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152419.3(HGSNAT):​c.1693G>C​(p.Gly565Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,782 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (91 hom.)
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.38
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077331364).
• BP6: Variant 8-43197919-G-C is Benign according to our data. Variant chr8-43197919-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 363152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0063 (959/152302) while in subpopulation NFE AF = 0.0105 (713/68040). AF 95% confidence interval is 0.00984. There are 8 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

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.1693G>C	p.Gly565Arg	missense	Exon 17 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.1780G>C	p.Gly594Arg	missense	Exon 18 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.1501G>C	p.Gly501Arg	missense	Exon 15 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.1693G>C	p.Gly565Arg	missense	Exon 17 of 18	ENSP00000368965.4	Q68CP4-2
	HGSNAT	ENST00000519705.1	TSL:1	n.1009G>C		non_coding_transcript_exon	Exon 3 of 4
	HGSNAT	ENST00000902460.1		c.1894G>C	p.Gly632Arg	missense	Exon 18 of 19	ENSP00000572519.1

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 959 AN: 152184 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00666 AC: 1659 AN: 249042 AF XY: 0.00707

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00478

Gnomad NFE exome AF: 0.00992

Gnomad OTH exome AF: 0.00563

GnomAD4 exome AF: 0.0111 AC: 16244 AN: 1461480 Hom.: 91 Cov.: 30 AF XY: 0.0109 AC XY: 7891 AN XY: 727034

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.00302 AC: 135 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00764 AC: 659 AN: 86230

European-Finnish (FIN) AF: 0.00476 AC: 254 AN: 53396

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14549 AN: 1111694

Other (OTH) AF: 0.00906 AC: 547 AN: 60368

GnomAD4 genome AF: 0.00630 AC: 959 AN: 152302 Hom.: 8 Cov.: 32 AF XY: 0.00624 AC XY: 465 AN XY: 74460

African (AFR) AF: 0.00257 AC: 107 AN: 41556

American (AMR) AF: 0.00379 AC: 58 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4826

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 713 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00852 Hom.: 4

Bravo AF: 0.00619

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00181 AC: 7

ESP6500EA AF: 0.0105 AC: 87

ExAC AF: 0.00633 AC: 765

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Mucopolysaccharidosis, MPS-III-C (3)
-	-	2	Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.86
Eigen	Benign	-0.21
Eigen_PC	Benign	0.00046
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.63	T
PhyloP100		2.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.24
Sift	Benign	0.72	T
Sift4G	Benign	0.85	T
Vest4		0.28
MVP		0.86
MPC		0.12
ClinPred		0.0078	T
GERP RS		5.1
gMVP		0.38
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148632988; hg19: chr8-43053062; COSMIC: COSV106099899; COSMIC: COSV106099899;