chr8-43199410-T-C

Variant names:

• chr8-43199410-T-C
• rs1126058
• NM_152419.3:c.1749T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001363227.2(HGSNAT):​c.1836T>C​(p.Tyr612Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,602,358 control chromosomes in the GnomAD database, including 798,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74872 hom., cov: 31)
  • Exomes 𝑓: 1.0 (723715 hom.)
• Consequence: HGSNAT NM_001363227.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -1.29
• Publications: 21 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-43199410-T-C is Benign according to our data. Variant chr8-43199410-T-C is described in ClinVar as Benign. ClinVar VariationId is 96503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363227.2. 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.1749T>C	p.Tyr583Tyr	synonymous	Exon 18 of 18	NP_689632.2
	HGSNAT	NM_001363227.2		c.1836T>C	p.Tyr612Tyr	synonymous	Exon 19 of 19	NP_001350156.1
	HGSNAT	NM_001363228.2		c.1557T>C	p.Tyr519Tyr	synonymous	Exon 16 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.1749T>C	p.Tyr583Tyr	synonymous	Exon 18 of 18	ENSP00000368965.4
	HGSNAT	ENST00000519705.1	TSL:1	n.1065T>C		non_coding_transcript_exon	Exon 4 of 4
	HGSNAT	ENST00000902460.1		c.1950T>C	p.Tyr650Tyr	synonymous	Exon 19 of 19	ENSP00000572519.1

Frequencies

GnomAD3 genomes AF: 0.991 AC: 150901 AN: 152200 Hom.: 74820 Cov.: 31

Gnomad AFR AF: 0.971

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.991

GnomAD2 exomes AF: 0.998 AC: 233261 AN: 233766 AF XY: 0.998

Gnomad AFR exome AF: 0.972

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1448722 AN: 1450040 Hom.: 723715 Cov.: 36 AF XY: 0.999 AC XY: 719697 AN XY: 720270

African (AFR) AF: 0.970 AC: 32268 AN: 33258

American (AMR) AF: 0.998 AC: 43048 AN: 43132

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25842 AN: 25842

East Asian (EAS) AF: 1.00 AC: 39491 AN: 39492

South Asian (SAS) AF: 1.00 AC: 83887 AN: 83900

European-Finnish (FIN) AF: 1.00 AC: 52878 AN: 52878

Middle Eastern (MID) AF: 0.995 AC: 5735 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1105653 AN: 1105744

Other (OTH) AF: 0.998 AC: 59920 AN: 60030

GnomAD4 genome AF: 0.991 AC: 151012 AN: 152318 Hom.: 74872 Cov.: 31 AF XY: 0.992 AC XY: 73854 AN XY: 74472

African (AFR) AF: 0.970 AC: 40333 AN: 41560

American (AMR) AF: 0.996 AC: 15250 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 1.00 AC: 4824 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68035 AN: 68040

Other (OTH) AF: 0.991 AC: 2096 AN: 2114

Alfa AF: 0.997 Hom.: 210754

Bravo AF: 0.990

Asia WGS AF: 0.998 AC: 3470 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Mucopolysaccharidosis, MPS-III-C (5)
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 (1)
-	-	1	Retinitis pigmentosa 73 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.21
DANN	Benign	0.39
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs1126058; hg19: chr8-43054553; COSMIC: COSV108135572; COSMIC: COSV108135572;