NM_005529.7:c.3337G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005529.7(HSPG2):c.3337G>A(p.Glu1113Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,609,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.151

Publications

1 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
Silverman-Handmaker type dyssegmental dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P
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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23830536).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005529.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	NM_005529.7	MANE Select	c.3337G>A	p.Glu1113Lys	missense	Exon 26 of 97	NP_005520.4
	HSPG2	NM_001291860.2		c.3340G>A	p.Glu1114Lys	missense	Exon 26 of 97	NP_001278789.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.3337G>A	p.Glu1113Lys	missense	Exon 26 of 97	ENSP00000363827.3	P98160
	HSPG2	ENST00000498495.1	TSL:2	n.241G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000293

AC:

AN:

238806

AF XY:

0.0000386

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1457126

Hom.:

Cov.:

AF XY:

0.0000387

AC XY:

AN XY:

724386

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33426

American (AMR)

AF:

0.0000226

AC:

AN:

44188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39570

South Asian (SAS)

AF:

0.0000586

AC:

AN:

85290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1110076

Other (OTH)

AF:

0.000249

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41514

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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:

0.000142

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

0.053

Eigen_PC

Benign

0.046

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0079

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

0.15

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

REVEL

Benign

0.091

Sift

Benign

0.28

Sift4G

Benign

0.14

Polyphen

0.92

Vest4

0.46

MutPred

0.56

Gain of ubiquitination at E1113 (P = 0.0104)

MVP

0.45

MPC

0.43

ClinPred

0.078

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

gMVP

0.38

Mutation Taster

=88/12

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over