NM_152419.3:c.28G>C

Variant names:

• chr8-43140524-G-C
• rs1802478718
• NM_152419.3:c.28G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152419.3(HGSNAT):​c.28G>C​(p.Ala10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000454 in 1,100,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.253
• 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):

• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16154596).

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.28G>C	p.Ala10Pro	missense	Exon 1 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.28G>C	p.Ala10Pro	missense	Exon 1 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.28G>C	p.Ala10Pro	missense	Exon 1 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.28G>C	p.Ala10Pro	missense	Exon 1 of 18	ENSP00000368965.4	Q68CP4-2
	HGSNAT	ENST00000520704.1	TSL:1	n.-123G>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000429109.1	E5RJC4
	HGSNAT	ENST00000520704.1	TSL:1	n.-123G>C		5_prime_UTR	Exon 1 of 10	ENSP00000429109.1	E5RJC4

Frequencies

GnomAD3 genomes AF: 0.0000202 AC: 3 AN: 148458 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000489

GnomAD4 exome AF: 0.00000210 AC: 2 AN: 952324 Hom.: 0 Cov.: 29 AF XY: 0.00000446 AC XY: 2 AN XY: 448804

African (AFR) AF: 0.00 AC: 0 AN: 18616

American (AMR) AF: 0.000234 AC: 1 AN: 4282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8954

East Asian (EAS) AF: 0.00 AC: 0 AN: 13552

South Asian (SAS) AF: 0.0000534 AC: 1 AN: 18736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839916

Other (OTH) AF: 0.00 AC: 0 AN: 34546

GnomAD4 genome AF: 0.0000202 AC: 3 AN: 148458 Hom.: 0 Cov.: 32 AF XY: 0.0000276 AC XY: 2 AN XY: 72336

African (AFR) AF: 0.00 AC: 0 AN: 41052

American (AMR) AF: 0.000134 AC: 2 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66626

Other (OTH) AF: 0.000489 AC: 1 AN: 2046

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.54	T
PhyloP100		-0.25
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.30
Sift	Benign	0.092	T
Sift4G	Benign	0.24	T
Vest4		0.16
MVP		0.67
MPC		0.13
ClinPred		0.31	T
GERP RS		0.93
PromoterAI		-0.028	Neutral
gMVP		0.55
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1802478718; hg19: chr8-42995667;