NM_005529.7:c.744T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005529.7(HSPG2):c.744T>C(p.Leu248Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,613,516 control chromosomes in the GnomAD database, including 115,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L248L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.45 ( 16892 hom., cov: 32)

Exomes 𝑓: 0.36 ( 98748 hom. )

Consequence

HSPG2
NM_005529.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.84

Publications

25 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.156).

BP6

Variant 1-21887634-A-G is Benign according to our data. Variant chr1-21887634-A-G is described in CliVar as Benign. Clinvar id is 295909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21887634-A-G is described in CliVar as Benign. Clinvar id is 295909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21887634-A-G is described in CliVar as Benign. Clinvar id is 295909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21887634-A-G is described in CliVar as Benign. Clinvar id is 295909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.744T>C	p.Leu248Leu	synonymous_variant	Exon 8 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.744T>C	p.Leu248Leu	synonymous_variant	Exon 8 of 97	1	NM_005529.7	ENSP00000363827.3	P98160
HSPG2	ENST00000374673.4 link	c.549T>C	p.Leu183Leu	synonymous_variant	Exon 6 of 7	3		ENSP00000497688.1	A0A3B3IT11
HSPG2	ENST00000412328.5 link	n.512T>C		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.449

AC:

68157

AN:

151792

Hom.:

16869

Cov.:

show subpopulations

Gnomad AFR

AF:

0.638

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.509

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.400

Gnomad FIN

AF:

0.357

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.336

Gnomad OTH

AF:

0.413

GnomAD2 exomes

AF:

0.419

AC:

104060

AN:

248518

AF XY:

0.404

show subpopulations

Gnomad AFR exome

AF:

0.640

Gnomad AMR exome

AF:

0.579

Gnomad ASJ exome

AF:

0.253

Gnomad EAS exome

AF:

0.628

Gnomad FIN exome

AF:

0.358

Gnomad NFE exome

AF:

0.334

Gnomad OTH exome

AF:

0.395

GnomAD4 exome

AF:

0.359

AC:

524289

AN:

1461606

Hom.:

98748

Cov.:

AF XY:

0.358

AC XY:

260001

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.646

AC:

21615

AN:

33472

American (AMR)

AF:

0.570

AC:

25498

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

6523

AN:

26134

East Asian (EAS)

AF:

0.596

AC:

23655

AN:

39700

South Asian (SAS)

AF:

0.407

AC:

35131

AN:

86252

European-Finnish (FIN)

AF:

0.365

AC:

19436

AN:

53278

Middle Eastern (MID)

AF:

0.321

AC:

1844

AN:

5742

European-Non Finnish (NFE)

AF:

0.331

AC:

367981

AN:

1111918

Other (OTH)

AF:

0.374

AC:

22606

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

20376

40752

61127

81503

101879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12224

24448

36672

48896

61120

<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:

0.449

AC:

68227

AN:

151910

Hom.:

16892

Cov.:

AF XY:

0.451

AC XY:

33474

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.638

AC:

26419

AN:

41424

American (AMR)

AF:

0.510

AC:

7799

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

843

AN:

3466

East Asian (EAS)

AF:

0.631

AC:

3247

AN:

5146

South Asian (SAS)

AF:

0.399

AC:

1923

AN:

4818

European-Finnish (FIN)

AF:

0.357

AC:

3766

AN:

10556

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.336

AC:

22837

AN:

67898

Other (OTH)

AF:

0.411

AC:

869

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1794

3587

5381

7174

8968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.378

Hom.:

12243

Bravo

AF:

0.466

Asia WGS

AF:

0.499

AC:

1736

AN:

3478

EpiCase

AF:

0.325

EpiControl

AF:

0.311

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Aug 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal Kniest-like syndrome

Benign:2

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Schwartz-Jampel syndrome

Benign:2

Jan 13, 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

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.54

(source)

DANN

Benign

0.90

PhyloP100

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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