1-21874505-C-T

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.3557G>A(p.Arg1186Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,613,214 control chromosomes in the GnomAD database, including 2,049 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. R1186W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.071 ( 742 hom., cov: 33)

Exomes 𝑓: 0.033 ( 1307 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0370

Publications

12 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=0.0016741753).

BP6

Variant 1-21874505-C-T is Benign according to our data. Variant chr1-21874505-C-T is described in ClinVar as Benign. ClinVar VariationId is 295860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.3557G>A	p.Arg1186Gln	missense_variant	Exon 28 of 97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSPG2	ENST00000374695.8 link	c.3557G>A	p.Arg1186Gln	missense_variant	Exon 28 of 97	1	NM_005529.7	ENSP00000363827.3	P98160
HSPG2	ENST00000427897.1 link	n.119G>A		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000397573.1	H0Y5A9
HSPG2	ENST00000498495.1 link	n.461G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0713

AC:

10847

AN:

152066

Hom.:

741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0401

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0318

Gnomad OTH

AF:

0.0694

GnomAD2 exomes

AF:

0.0343

AC:

8565

AN:

250006

AF XY:

0.0317

show subpopulations

Gnomad AFR exome

AF:

0.172

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0285

Gnomad NFE exome

AF:

0.0323

Gnomad OTH exome

AF:

0.0370

GnomAD4 exome

AF:

0.0331

AC:

48329

AN:

1461030

Hom.:

1307

Cov.:

AF XY:

0.0322

AC XY:

23426

AN XY:

726818

show subpopulations

African (AFR)

AF:

0.187

AC:

6272

AN:

33464

American (AMR)

AF:

0.0235

AC:

1050

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

464

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0145

AC:

1251

AN:

86212

European-Finnish (FIN)

AF:

0.0305

AC:

1622

AN:

53228

Middle Eastern (MID)

AF:

0.0417

AC:

222

AN:

5320

European-Non Finnish (NFE)

AF:

0.0316

AC:

35187

AN:

1111928

Other (OTH)

AF:

0.0374

AC:

2257

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2730

5461

8191

10922

13652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1370

2740

4110

5480

6850

<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:

0.0714

AC:

10873

AN:

152184

Hom.:

742

Cov.:

AF XY:

0.0692

AC XY:

5145

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.179

AC:

7435

AN:

41496

American (AMR)

AF:

0.0401

AC:

613

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0261

AC:

277

AN:

10606

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0318

AC:

2160

AN:

67998

Other (OTH)

AF:

0.0687

AC:

145

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

488

975

1463

1950

2438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0431

Hom.:

592

Bravo

AF:

0.0760

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0345

AC:

133

ESP6500AA

AF:

0.174

AC:

768

ESP6500EA

AF:

0.0298

AC:

256

ExAC

AF:

0.0371

AC:

4500

Asia WGS

AF:

0.0170

AC:

AN:

3476

EpiCase

AF:

0.0296

EpiControl

AF:

0.0287

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal Kniest-like syndrome

Benign:1

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. -

Schwartz-Jampel syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

0.065

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.080

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.085

PhyloP100

0.037

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.54

REVEL

Benign

0.048

Sift

Benign

0.59

Sift4G

Benign

0.27

Polyphen

0.0020

Vest4

0.036

MPC

0.24

ClinPred

0.0031

GERP RS

0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.20

Mutation Taster

=95/5

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