rs121908285

Variant names:

• chr8-43182162-C-T
• rs121908285
• NM_152419.3:c.1030C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-43182162-C-T
• chr8-43182162-C-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM5 PP3_Strong PP5

The NM_152419.3(HGSNAT):​c.1030C>T​(p.Arg344Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,678 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: "SCV006323072: Relevant functional assessments of this variant are available in the literature (PMID:19823585, 20583299)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R344H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:1 O:1
• Conservation: PhyloP100: 4.44
• Publications: 17 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 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006323072: Relevant functional assessments of this variant are available in the literature (PMID: 19823585, 20583299).; SCV000938835: Experimental studies have shown that this missense change affects HGSNAT function (PMID: 19823584, 20583299, 20825431).; SCV005418657: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV003801277: At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 19823584). The most pronounced variant effect results in approximately 10% of normal heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) activity in-vitro.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-43182163-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 551378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 8-43182162-C-T is Pathogenic according to our data. Variant chr8-43182162-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1237.

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.1030C>T	p.Arg344Cys	missense	Exon 11 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.1030C>T	p.Arg344Cys	missense	Exon 11 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.838C>T	p.Arg280Cys	missense	Exon 9 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.1030C>T	p.Arg344Cys	missense	Exon 11 of 18	ENSP00000368965.4	Q68CP4-2
	HGSNAT	ENST00000902460.1		c.1030C>T	p.Arg344Cys	missense	Exon 11 of 19	ENSP00000572519.1
	HGSNAT	ENST00000902456.1		c.1030C>T	p.Arg344Cys	missense	Exon 11 of 19	ENSP00000572515.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249274 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461504 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 727056

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111692

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00000497 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis, MPS-III-C (4)
4	-	-	not provided (4)
3	-	-	Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (3)
-	1	-	Retinal dystrophy (1)
1	-	-	Sanfilippo syndrome (1)
-	-	-	Mucopolysaccharidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		4.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MVP		0.94
MPC		0.61
ClinPred		1.0	D
GERP RS		4.2
gMVP		0.86
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs121908285; hg19: chr8-43037305; COSMIC: COSV107397093; COSMIC: COSV107397093;