rs2228349

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.9502G>A(p.Ala3168Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 1,608,368 control chromosomes in the GnomAD database, including 6,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3168G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.098 ( 860 hom., cov: 33)

Exomes 𝑓: 0.082 ( 5507 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.959

Publications

16 publications found

Variant links:

Genes affected

HSPG2 (HGNC:5273): (heparan sulfate proteoglycan 2) This gene encodes the perlecan protein, which consists of a core protein to which three long chains of glycosaminoglycans (heparan sulfate or chondroitin sulfate) are attached. The perlecan protein is a large multidomain proteoglycan that binds to and cross-links many extracellular matrix components and cell-surface molecules. It has been shown that this protein interacts with laminin, prolargin, collagen type IV, FGFBP1, FBLN2, FGF7 and transthyretin, etc., and it plays essential roles in multiple biological activities. Perlecan is a key component of the vascular extracellular matrix, where it helps to maintain the endothelial barrier function. It is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. It can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation. It is a major component of basement membranes, where it is involved in the stabilization of other molecules as well as being involved with glomerular permeability to macromolecules and cell adhesion. Mutations in this gene cause Schwartz-Jampel syndrome type 1, Silverman-Handmaker type of dyssegmental dysplasia, and tardive dyskinesia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

HSPG2 Gene-Disease associations (from GenCC):

Schwartz-Jampel syndrome type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
Silverman-Handmaker type dyssegmental dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Schwartz-Jampel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HSPG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002572894).

BP6

Variant 1-21841112-C-T is Benign according to our data. Variant chr1-21841112-C-T is described in ClinVar as Benign. ClinVar VariationId is 295758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.9502G>A	p.Ala3168Thr	missense_variant	Exon 71 of 97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.9502G>A	p.Ala3168Thr	missense_variant	Exon 71 of 97	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.0980

AC:

14919

AN:

152172

Hom.:

859

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.0663

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.0560

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0804

Gnomad OTH

AF:

0.102

GnomAD2 exomes

AF:

0.0738

AC:

17383

AN:

235514

AF XY:

0.0764

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.0403

Gnomad ASJ exome

AF:

0.0562

Gnomad EAS exome

AF:

0.000228

Gnomad FIN exome

AF:

0.0580

Gnomad NFE exome

AF:

0.0788

Gnomad OTH exome

AF:

0.0777

GnomAD4 exome

AF:

0.0824

AC:

119917

AN:

1456078

Hom.:

5507

Cov.:

AF XY:

0.0833

AC XY:

60331

AN XY:

724050

show subpopulations

African (AFR)

AF:

0.173

AC:

5786

AN:

33358

American (AMR)

AF:

0.0431

AC:

1897

AN:

43966

Ashkenazi Jewish (ASJ)

AF:

0.0563

AC:

1461

AN:

25964

East Asian (EAS)

AF:

0.000279

AC:

AN:

39480

South Asian (SAS)

AF:

0.116

AC:

9939

AN:

85612

European-Finnish (FIN)

AF:

0.0597

AC:

3115

AN:

52162

Middle Eastern (MID)

AF:

0.0996

AC:

570

AN:

5722

European-Non Finnish (NFE)

AF:

0.0831

AC:

92252

AN:

1109738

Other (OTH)

AF:

0.0813

AC:

4886

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

6179

12358

18537

24716

30895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3454

6908

10362

13816

17270

<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:

0.0981

AC:

14940

AN:

152290

Hom.:

860

Cov.:

AF XY:

0.0944

AC XY:

7029

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.162

AC:

6745

AN:

41546

American (AMR)

AF:

0.0663

AC:

1014

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

185

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.110

AC:

532

AN:

4832

European-Finnish (FIN)

AF:

0.0560

AC:

595

AN:

10622

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0804

AC:

5471

AN:

68018

Other (OTH)

AF:

0.101

AC:

214

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

692

1384

2076

2768

3460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.0849

Hom.:

1637

Bravo

AF:

0.0994

TwinsUK

AF:

0.0930

AC:

345

ALSPAC

AF:

0.0893

AC:

344

ESP6500AA

AF:

0.158

AC:

693

ESP6500EA

AF:

0.0755

AC:

648

ExAC

AF:

0.0747

AC:

9041

Asia WGS

AF:

0.0520

AC:

181

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal Kniest-like syndrome

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

Schwartz-Jampel syndrome

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.6

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.15

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

PhyloP100

0.96

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Benign

0.27

Sift4G

Benign

0.19

Polyphen

0.0060

Vest4

0.043

MPC

0.21

ClinPred

0.0057

GERP RS

-0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.077

gMVP

0.36

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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