8-43140494-G-A

Variant names:

• chr8-43140494-G-A
• rs1162962895
• NM_152419.3:c.-3G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152419.3(HGSNAT):​c.-3G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000114 in 873,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: HGSNAT NM_152419.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• Publications: 0 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: Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 73

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.118).

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.-3G>A		5_prime_UTR	Exon 1 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.-3G>A		5_prime_UTR	Exon 1 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.-3G>A		5_prime_UTR	Exon 1 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.-3G>A		5_prime_UTR	Exon 1 of 18	ENSP00000368965.4	Q68CP4-2
	HGSNAT	ENST00000902460.1		c.-3G>A		5_prime_UTR	Exon 1 of 19	ENSP00000572519.1
	HGSNAT	ENST00000902456.1		c.-3G>A		5_prime_UTR	Exon 1 of 19	ENSP00000572515.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000114 AC: 1 AN: 873544 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 407680

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16670

American (AMR) AF: 0.00 AC: 0 AN: 2256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6358

East Asian (EAS) AF: 0.00 AC: 0 AN: 5970

South Asian (SAS) AF: 0.00 AC: 0 AN: 17574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1842

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 788416

Other (OTH) AF: 0.00 AC: 0 AN: 29762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.9
DANN	Benign	0.86
PhyloP100		0.087
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs1162962895; hg19: chr8-42995637;