12-64752752-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002076.4(GNS):c.198G>A(p.Pro66Pro) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.442

Publications

24 publications found

Variant links:

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]

GNS Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 3D
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

GNS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 94029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
GNS	NM_002076.4 link	c.198G>A	p.Pro66Pro	synonymous_variant	Exon 2 of 14	ENST00000258145.8	NP_002067.1	P15586-1A0A024RBC5Q7Z3X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNS	ENST00000258145.8 link	c.198G>A	p.Pro66Pro	synonymous_variant	Exon 2 of 14	1	NM_002076.4	ENSP00000258145.3		P15586-1

Frequencies

GnomAD3 genomes

AF:

0.695

AC:

105697

AN:

152032

Hom.:

38235

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.641

AC:

157726

AN:

245972

AF XY:

0.638

show subpopulations

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 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.:

AF XY:

0.604

AC XY:

393305

AN XY:

650962

show subpopulations

African (AFR)

AF:

0.908

AC:

26603

AN:

29290

American (AMR)

AF:

0.571

AC:

25180

AN:

44112

Ashkenazi Jewish (ASJ)

AF:

0.509

AC:

12664

AN:

24888

East Asian (EAS)

AF:

0.870

AC:

33728

AN:

38754

South Asian (SAS)

AF:

0.662

AC:

54453

AN:

82290

European-Finnish (FIN)

AF:

0.634

AC:

33597

AN:

52990

Middle Eastern (MID)

AF:

0.573

AC:

3120

AN:

5444

European-Non Finnish (NFE)

AF:

0.578

AC:

554185

AN:

959352

Other (OTH)

AF:

0.615

AC:

33646

AN:

54678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

13128

26256

39384

52512

65640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14352

28704

43056

57408

71760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.695

AC:

105795

AN:

152150

Hom.:

38282

Cov.:

AF XY:

0.696

AC XY:

51742

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.904

AC:

37535

AN:

41534

American (AMR)

AF:

0.618

AC:

9454

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.503

AC:

1745

AN:

3470

East Asian (EAS)

AF:

0.878

AC:

4545

AN:

5176

South Asian (SAS)

AF:

0.679

AC:

3278

AN:

4826

European-Finnish (FIN)

AF:

0.628

AC:

6639

AN:

10564

Middle Eastern (MID)

AF:

0.548

AC:

161

AN:

294

European-Non Finnish (NFE)

AF:

0.597

AC:

40590

AN:

67976

Other (OTH)

AF:

0.665

AC:

1405

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1561

3122

4684

6245

7806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.610

Hom.:

19483

Bravo

AF:

0.700

Asia WGS

AF:

0.773

AC:

2687

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-D

Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 03, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sanfilippo syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.7

(source)

DANN

Benign

0.48

PhyloP100

-0.44

PromoterAI

-0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over