rs121908282

Variant names:

• chr8-43173740-C-A
• NM_152419.3:c.848C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-43173740-C-A
• chr8-43173740-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_152419.3(HGSNAT):​c.848C>A​(p.Pro283Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P283L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity HGNAT_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_152419.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-43173740-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3	c.848C>A	p.Pro283Gln	missense_variant	Exon 9 of 18	ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGSNAT	ENST00000379644.9	c.848C>A	p.Pro283Gln	missense_variant	Exon 9 of 18	2	NM_152419.3	ENSP00000368965.4
HGSNAT	ENST00000520704.1	n.*297C>A		non_coding_transcript_exon_variant	Exon 10 of 10	1		ENSP00000429109.1
HGSNAT	ENST00000520704.1	n.*297C>A		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000429109.1
HGSNAT	ENST00000522082.5	c.89C>A	p.Pro30Gln	missense_variant	Exon 2 of 6	4		ENSP00000430151.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460280 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.90
MVP		0.94
MPC		0.50
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.92

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-43028883; COSMIC: COSV101108323; COSMIC: COSV101108323;