rs2290501

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.7873+25A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,542 control chromosomes in the GnomAD database, including 93,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11185 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82755 hom. )

Consequence

HSPG2
NM_005529.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.665

Publications

22 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.03).

BP6

Variant 1-21847933-T-G is Benign according to our data. Variant chr1-21847933-T-G is described in ClinVar as Benign. ClinVar VariationId is 1256801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.7873+25A>C		intron_variant	Intron 60 of 96	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.7873+25A>C		intron_variant	Intron 60 of 96	1	NM_005529.7	ENSP00000363827.3		P98160
HSPG2	ENST00000453796.1 link	n.26A>C		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56142

AN:

151926

Hom.:

11153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.525

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.350

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.482

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.312

Gnomad OTH

AF:

0.367

GnomAD2 exomes

AF:

0.325

AC:

81523

AN:

250788

AF XY:

0.333

show subpopulations

Gnomad AFR exome

AF:

0.525

Gnomad AMR exome

AF:

0.208

Gnomad ASJ exome

AF:

0.350

Gnomad EAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.314

Gnomad OTH exome

AF:

0.313

GnomAD4 exome

AF:

0.331

AC:

483107

AN:

1461498

Hom.:

82755

Cov.:

AF XY:

0.334

AC XY:

243072

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.541

AC:

18109

AN:

33480

American (AMR)

AF:

0.216

AC:

9643

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

9318

AN:

26136

East Asian (EAS)

AF:

0.182

AC:

7241

AN:

39700

South Asian (SAS)

AF:

0.479

AC:

41320

AN:

86258

European-Finnish (FIN)

AF:

0.334

AC:

17747

AN:

53080

Middle Eastern (MID)

AF:

0.317

AC:

1831

AN:

5768

European-Non Finnish (NFE)

AF:

0.322

AC:

357624

AN:

1111966

Other (OTH)

AF:

0.336

AC:

20274

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

21027

42053

63080

84106

105133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11898

23796

35694

47592

59490

<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:

0.370

AC:

56229

AN:

152044

Hom.:

11185

Cov.:

AF XY:

0.366

AC XY:

27204

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.526

AC:

21797

AN:

41454

American (AMR)

AF:

0.267

AC:

4086

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.350

AC:

1216

AN:

3472

East Asian (EAS)

AF:

0.173

AC:

896

AN:

5168

South Asian (SAS)

AF:

0.482

AC:

2320

AN:

4812

European-Finnish (FIN)

AF:

0.334

AC:

3534

AN:

10590

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.312

AC:

21170

AN:

67954

Other (OTH)

AF:

0.368

AC:

776

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1742

3483

5225

6966

8708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.330

Hom.:

16905

Bravo

AF:

0.366

Asia WGS

AF:

0.350

AC:

1217

AN:

3478

EpiCase

AF:

0.297

EpiControl

AF:

0.309

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Lethal Kniest-like syndrome

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Schwartz-Jampel syndrome

Benign:1

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

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.0

(source)

DANN

Benign

0.54

PhyloP100

-0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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