rs1554532014

Variant names:

• chr8-43172385-T-G
• rs1554532014
• NM_152419.3:c.819T>G

Variant summary

Our verdict is Uncertain significance. The variant received 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 (no stars). 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 no assertion criteria provided U:1
• Conservation: PhyloP100: 0.302
• Publications: 2 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):

• mucopolysaccharidosis type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• mucopolysaccharidosis type 3C

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics, G2P
• retinitis pigmentosa 73

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId 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 rank	MANE	Protein	UniProt
HGSNAT	NM_152419.3	c.819T>G	p.Asn273Lys	missense_variant, splice_region_variant	Exon 8 of 18	ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGSNAT	ENST00000379644.9	c.819T>G	p.Asn273Lys	missense_variant, splice_region_variant	Exon 8 of 18	2	NM_152419.3	ENSP00000368965.4
HGSNAT	ENST00000520704.1	n.*268T>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 10	1		ENSP00000429109.1
HGSNAT	ENST00000520704.1	n.*268T>G		3_prime_UTR_variant	Exon 9 of 10	1		ENSP00000429109.1
HGSNAT	ENST00000522082.5	c.60T>G	p.Asn20Lys	missense_variant, splice_region_variant	Exon 1 of 6	4		ENSP00000430151.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C Uncertain:1

May 10, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
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
PhyloP100		0.30
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
PromoterAI		-0.026	Neutral
gMVP		0.90
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.14
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs1554532014; hg19: chr8-43027528;