chr12-64752752-C-T

Position:

• chr12-64752752-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002076.4(GNS):​c.198G>A​(p.Pro66=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,443,948 control chromosomes in the GnomAD database, including 277,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P66P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.70 (38282 hom., cov: 32)
  • Exomes 𝑓: 0.60 (239134 hom.)
• Consequence: GNS NM_002076.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.442

Genes affected

GNS (HGNC:4422): (glucosamine (N-acetyl)-6-sulfatase) The product of this gene is a lysosomal enzyme found in all cells. It is involved in the catabolism of heparin, heparan sulphate, and keratan sulphate. Deficiency of this enzyme results in the accumulation of undegraded substrate and the lysosomal storage disorder mucopolysaccharidosis type IIID (Sanfilippo D syndrome). Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 12-64752752-C-T is Benign according to our data. Variant chr12-64752752-C-T is described in ClinVar as [Benign]. Clinvar id is 94029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64752752-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.442 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNS	NM_002076.4	c.198G>A	p.Pro66=	synonymous_variant	2/14	ENST00000258145.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNS	ENST00000258145.8	c.198G>A	p.Pro66=	synonymous_variant	2/14	1	NM_002076.4	P1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105697 AN: 152032 Hom.: 38235 Cov.: 32

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.661

GnomAD3 exomes AF: 0.641 AC: 157726 AN: 245972 Hom.: 52130 AF XY: 0.638 AC XY: 84886 AN XY: 132960

Gnomad AFR exome AF: 0.912

Gnomad AMR exome AF: 0.565

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.878

Gnomad SAS exome AF: 0.670

Gnomad FIN exome AF: 0.636

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.602 AC: 777176 AN: 1291798 Hom.: 239134 Cov.: 22 AF XY: 0.604 AC XY: 393305 AN XY: 650962

Gnomad4 AFR exome AF: 0.908

Gnomad4 AMR exome AF: 0.571

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.870

Gnomad4 SAS exome AF: 0.662

Gnomad4 FIN exome AF: 0.634

Gnomad4 NFE exome AF: 0.578

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.695 AC: 105795 AN: 152150 Hom.: 38282 Cov.: 32 AF XY: 0.696 AC XY: 51742 AN XY: 74372

Gnomad4 AFR AF: 0.904

Gnomad4 AMR AF: 0.618

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.878

Gnomad4 SAS AF: 0.679

Gnomad4 FIN AF: 0.628

Gnomad4 NFE AF: 0.597

Gnomad4 OTH AF: 0.665

Alfa AF: 0.596 Hom.: 12517

Bravo AF: 0.700

Asia WGS AF: 0.773 AC: 2687 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-D Benign:6

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2016	Variant summary: The c.198G>A (p.Pro66=) in GNS gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.0655 (75159/114750 chrs tested), indicating that it is an ancestral allele. The observed frequency exceeds the maximum expected allele frequency for a pathogenic GNS variant of 0.0011 suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign by a reputable database/clinical laboratory. Taking together, based on the prevalence in general population the variant was classified as Benign. -

Sanfilippo syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.7
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1147096; hg19: chr12-65146532;