8-43140516-C-T

Variant names:

• chr8-43140516-C-T
• NM_152419.3:c.20C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_152419.3(HGSNAT):​c.20C>T​(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 931,868 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.978

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Lumenal, vesicle (size 189) in uniprot entity HGNAT_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_152419.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16137758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 18	ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGSNAT	ENST00000379644.9	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 18	2	NM_152419.3	ENSP00000368965.4
HGSNAT	ENST00000520704.1	n.-131C>T		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000429109.1
HGSNAT	ENST00000520704.1	n.-131C>T		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000429109.1
HGSNAT	ENST00000517319.1	n.20C>T		non_coding_transcript_exon_variant	Exon 1 of 5	4		ENSP00000430032.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000322 AC: 3 AN: 931868 Hom.: 0 Cov.: 29 AF XY: 0.00000456 AC XY: 2 AN XY: 438126

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: 0.00000363

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 02, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	12
DANN	Uncertain	0.98
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.40	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.066
MVP		0.53
MPC		0.10
ClinPred		0.49	T
GERP RS		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.37

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-42995659;