NM_005529.7:c.8939T>A

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.8939T>A(p.Leu2980His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,609,560 control chromosomes in the GnomAD database, including 3,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 179 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2886 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.37

Publications

13 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=0.004461229).

BP6

Variant 1-21842352-A-T is Benign according to our data. Variant chr1-21842352-A-T is described in ClinVar as Benign. ClinVar VariationId is 295765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.8939T>A	p.Leu2980His	missense_variant	Exon 68 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.8939T>A	p.Leu2980His	missense_variant	Exon 68 of 97	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.0405

AC:

6167

AN:

152102

Hom.:

177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00951

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.0343

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0586

Gnomad OTH

AF:

0.0458

GnomAD2 exomes

AF:

0.0490

AC:

12066

AN:

246234

AF XY:

0.0539

show subpopulations

Gnomad AFR exome

AF:

0.00839

Gnomad AMR exome

AF:

0.0237

Gnomad ASJ exome

AF:

0.0421

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.0441

Gnomad NFE exome

AF:

0.0568

Gnomad OTH exome

AF:

0.0514

GnomAD4 exome

AF:

0.0581

AC:

84728

AN:

1457340

Hom.:

2886

Cov.:

AF XY:

0.0601

AC XY:

43549

AN XY:

724330

show subpopulations

African (AFR)

AF:

0.00811

AC:

271

AN:

33422

American (AMR)

AF:

0.0249

AC:

1106

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.0426

AC:

1110

AN:

26050

East Asian (EAS)

AF:

0.000202

AC:

AN:

39588

South Asian (SAS)

AF:

0.109

AC:

9331

AN:

85938

European-Finnish (FIN)

AF:

0.0450

AC:

2357

AN:

52376

Middle Eastern (MID)

AF:

0.0701

AC:

403

AN:

5750

European-Non Finnish (NFE)

AF:

0.0603

AC:

66890

AN:

1109548

Other (OTH)

AF:

0.0540

AC:

3252

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

4543

9086

13630

18173

22716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2480

4960

7440

9920

12400

<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:

0.0406

AC:

6175

AN:

152220

Hom.:

179

Cov.:

AF XY:

0.0401

AC XY:

2983

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00961

AC:

399

AN:

41534

American (AMR)

AF:

0.0342

AC:

523

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

139

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.104

AC:

503

AN:

4824

European-Finnish (FIN)

AF:

0.0432

AC:

458

AN:

10604

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0586

AC:

3986

AN:

68010

Other (OTH)

AF:

0.0454

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

330

660

989

1319

1649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0540

Hom.:

198

Bravo

AF:

0.0365

TwinsUK

AF:

0.0647

AC:

240

ALSPAC

AF:

0.0623

AC:

240

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0557

AC:

479

ExAC

AF:

0.0496

AC:

6024

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Aug 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

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 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:2

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

Connective tissue disorder

Benign:1

Jun 03, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.041

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.066

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.024

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

PhyloP100

3.4

PrimateAI

Benign

0.35

PROVEAN

Benign

2.3

REVEL

Benign

0.070

Sift

Benign

1.0

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.036

MPC

0.26

ClinPred

0.00051

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.26

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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