rs1554532014

chr8-43172385-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_152419.3(HGSNAT):c.819T>G(p.Asn273Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N273I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGSNAT NM_152419.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002068
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.302

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-43172384-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2921769.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGSNAT	NM_152419.3	c.819T>G	p.Asn273Lys	missense_variant, splice_region_variant	8/18	ENST00000379644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGSNAT	ENST00000379644.9	c.819T>G	p.Asn273Lys	missense_variant, splice_region_variant	8/18	2	NM_152419.3	P3
HGSNAT	ENST00000520704.1	c.*268T>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	9/10	1
HGSNAT	ENST00000522082.5	c.60T>G	p.Asn20Lys	missense_variant, splice_region_variant	1/6	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.54	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.98
MVP		0.86
MPC		0.54
ClinPred		1.0	D
GERP RS		-1.5
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554532014; hg19: chr8-43027528;