rs139794766

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS1

The NM_005529.7(HSPG2):c.5297C>T(p.Ala1766Val) variant causes a missense change. The variant allele was found at a frequency of 0.000464 in 1,613,514 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1766T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 1 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 5.39

Publications

5 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 -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21857383-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2506375.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.011281133).

BP6

Variant 1-21857382-G-A is Benign according to our data. Variant chr1-21857382-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 295834.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000328 (50/152264) while in subpopulation SAS AF = 0.00249 (12/4824). AF 95% confidence interval is 0.00144. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.5297C>T	p.Ala1766Val	missense_variant	Exon 43 of 97	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.5297C>T	p.Ala1766Val	missense_variant	Exon 43 of 97	1	NM_005529.7	ENSP00000363827.3

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000584

AC:

146

AN:

250104

AF XY:

0.000732

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000372

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000478

AC:

699

AN:

1461250

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

401

AN XY:

726926

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33474

American (AMR)

AF:

0.000425

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00293

AC:

253

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52916

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000335

AC:

373

AN:

1111906

Other (OTH)

AF:

0.000447

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000328

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41534

American (AMR)

AF:

0.000261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00249

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000515

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000708

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The A1766V variant in the HSPG2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A1766V variant is observed in 92/30776 (0.3%) alleles from individuals of South Asian background in large population cohorts, and 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016). The A1766V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret A1766V as a variant of uncertain significance. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HSPG2 p.Ala1766Val variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs139794766) and ClinVar (classified as likely benign by Athena Diagnostics and as uncertain significance by Illumina and GeneDx). The variant was identified in control databases in 162 of 281466 chromosomes at a frequency of 0.0005756 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 92 of 30610 chromosomes (freq: 0.003006), Other in 6 of 7204 chromosomes (freq: 0.000833), European (non-Finnish) in 53 of 128280 chromosomes (freq: 0.000413), Latino in 8 of 35398 chromosomes (freq: 0.000226) and African in 3 of 24894 chromosomes (freq: 0.000121), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Ala1766 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Connective tissue disorder

Uncertain:1

Dec 02, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal Kniest-like syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Aug 18, 2016

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HSPG2-related disorder

Benign:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Schwartz-Jampel syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.81

M_CAP

Benign

0.0056

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PhyloP100

5.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.5

REVEL

Benign

0.043

Sift

Benign

0.18

Sift4G

Benign

0.70

Polyphen

0.77

Vest4

0.19

MVP

0.59

MPC

0.26

ClinPred

0.098

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.28

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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