NM_152419.3:c.12G>T

Variant names:

• chr8-43140508-G-T
• rs1018475767
• NM_152419.3:c.12G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_152419.3(HGSNAT):​c.12G>T​(p.Ala4Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000675 in 148,084 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HGSNAT NM_152419.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.412
• 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: Orphanet, Genomics England PanelApp, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 73

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-43140508-G-T is Benign according to our data. Variant chr8-43140508-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1143112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.412 with no splicing effect.

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.12G>T	p.Ala4Ala	synonymous	Exon 1 of 18	NP_689632.2
	HGSNAT	NM_001363229.2		c.-822G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001350158.1
	HGSNAT	NM_001363227.2		c.12G>T	p.Ala4Ala	synonymous	Exon 1 of 19	NP_001350156.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGSNAT	ENST00000379644.9	TSL:2 MANE Select	c.12G>T	p.Ala4Ala	synonymous	Exon 1 of 18	ENSP00000368965.4	Q68CP4-2
	HGSNAT	ENST00000520704.1	TSL:1	n.-139G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000429109.1	E5RJC4
	HGSNAT	ENST00000520704.1	TSL:1	n.-139G>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000429109.1	E5RJC4

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000490

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 910198 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 426748

African (AFR) AF: 0.00 AC: 0 AN: 17624

American (AMR) AF: 0.00 AC: 0 AN: 3124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7518

East Asian (EAS) AF: 0.00 AC: 0 AN: 9194

South Asian (SAS) AF: 0.00 AC: 0 AN: 17966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2038

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 813018

Other (OTH) AF: 0.00 AC: 0 AN: 31932

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148084 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 72112

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

African (AFR) AF: 0.00 AC: 0 AN: 41026

American (AMR) AF: 0.00 AC: 0 AN: 14892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66456

Other (OTH) AF: 0.000490 AC: 1 AN: 2042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.7
DANN	Benign	0.53
PhyloP100		-0.41
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1018475767; hg19: chr8-42995651;