rs2228349

Positions:

chr1-21841112-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.9502G>A(p.Ala3168Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 1,608,368 control chromosomes in the GnomAD database, including 6,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3168G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.098 ( 860 hom., cov: 33)

Exomes 𝑓: 0.082 ( 5507 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.959

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HSPG2. . Gene score misZ 1.1367 (greater than the threshold 3.09). Trascript score misZ 3.3999 (greater than threshold 3.09). GenCC has associacion of gene with Silverman-Handmaker type dyssegmental dysplasia, Schwartz-Jampel syndrome type 1, Schwartz-Jampel syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.002572894).

BP6

Variant 1-21841112-C-T is Benign according to our data. Variant chr1-21841112-C-T is described in ClinVar as [Benign]. Clinvar id is 295758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.9502G>A	p.Ala3168Thr	missense_variant	71/97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 linkuse as main transcript	c.9502G>A	p.Ala3168Thr	missense_variant	71/97	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.0980

AC:

14919

AN:

152172

Hom.:

859

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.0663

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.0560

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0804

Gnomad OTH

AF:

0.102

GnomAD3 exomes

AF:

0.0738

AC:

17383

AN:

235514

Hom.:

803

AF XY:

0.0764

AC XY:

9817

AN XY:

128572

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.0403

Gnomad ASJ exome

AF:

0.0562

Gnomad EAS exome

AF:

0.000228

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0580

Gnomad NFE exome

AF:

0.0788

Gnomad OTH exome

AF:

0.0777

GnomAD4 exome

AF:

0.0824

AC:

119917

AN:

1456078

Hom.:

5507

Cov.:

AF XY:

0.0833

AC XY:

60331

AN XY:

724050

show subpopulations

Gnomad4 AFR exome

AF:

0.173

Gnomad4 AMR exome

AF:

0.0431

Gnomad4 ASJ exome

AF:

0.0563

Gnomad4 EAS exome

AF:

0.000279

Gnomad4 SAS exome

AF:

0.116

Gnomad4 FIN exome

AF:

0.0597

Gnomad4 NFE exome

AF:

0.0831

Gnomad4 OTH exome

AF:

0.0813

GnomAD4 genome

AF:

0.0981

AC:

14940

AN:

152290

Hom.:

860

Cov.:

AF XY:

0.0944

AC XY:

7029

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.162

Gnomad4 AMR

AF:

0.0663

Gnomad4 ASJ

AF:

0.0533

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.0560

Gnomad4 NFE

AF:

0.0804

Gnomad4 OTH

AF:

0.101

Alfa

AF:

0.0811

Hom.:

963

Bravo

AF:

0.0994

TwinsUK

AF:

0.0930

AC:

345

ALSPAC

AF:

0.0893

AC:

344

ESP6500AA

AF:

0.158

AC:

693

ESP6500EA

AF:

0.0755

AC:

648

ExAC

AF:

0.0747

AC:

9041

Asia WGS

AF:

0.0520

AC:

181

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Lethal Kniest-like syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.6

DANN

Benign

0.94

DEOGEN2

Benign

0.15

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Benign

0.27

Sift4G

Benign

0.19

Polyphen

0.0060

Vest4

0.043

MPC

0.21

ClinPred

0.0057

GERP RS

-0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.077

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over