1-21833550-C-T

Position:

chr1-21833550-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.10895G>A(p.Arg3632Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,613,860 control chromosomes in the GnomAD database, including 6,534 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 (★★).

Frequency

Genomes: 𝑓 0.10 ( 925 hom., cov: 33)

Exomes 𝑓: 0.083 ( 5609 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0570

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=0.0018043518).

BP6

Variant 1-21833550-C-T is Benign according to our data. Variant chr1-21833550-C-T is described in ClinVar as [Benign]. Clinvar id is 295727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 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.10895G>A	p.Arg3632Gln	missense_variant	79/97	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HSPG2	ENST00000374695.8 linkuse as main transcript	c.10895G>A	p.Arg3632Gln	missense_variant	79/97	1	NM_005529.7	ENSP00000363827	P1
HSPG2	ENST00000635682.1 linkuse as main transcript	c.29G>A	p.Arg10Gln	missense_variant	1/9	5		ENSP00000489161
HSPG2	ENST00000471322.2 linkuse as main transcript	n.1250G>A		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15308

AN:

151934

Hom.:

924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.171

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.0678

Gnomad ASJ

AF:

0.0530

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.0561

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0805

Gnomad OTH

AF:

0.106

GnomAD3 exomes

AF:

0.0757

AC:

19005

AN:

251202

Hom.:

933

AF XY:

0.0776

AC XY:

10538

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.0410

Gnomad ASJ exome

AF:

0.0566

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0593

Gnomad NFE exome

AF:

0.0796

Gnomad OTH exome

AF:

0.0794

GnomAD4 exome

AF:

0.0826

AC:

120778

AN:

1461808

Hom.:

5609

Cov.:

AF XY:

0.0836

AC XY:

60766

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.183

Gnomad4 AMR exome

AF:

0.0439

Gnomad4 ASJ exome

AF:

0.0565

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.116

Gnomad4 FIN exome

AF:

0.0598

Gnomad4 NFE exome

AF:

0.0831

Gnomad4 OTH exome

AF:

0.0825

GnomAD4 genome

AF:

0.101

AC:

15329

AN:

152052

Hom.:

925

Cov.:

AF XY:

0.0968

AC XY:

7194

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.171

Gnomad4 AMR

AF:

0.0678

Gnomad4 ASJ

AF:

0.0530

Gnomad4 EAS

AF:

0.000389

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.0561

Gnomad4 NFE

AF:

0.0805

Gnomad4 OTH

AF:

0.105

Alfa

AF:

0.0805

Hom.:

1116

Bravo

AF:

0.103

TwinsUK

AF:

0.0925

AC:

343

ALSPAC

AF:

0.0893

AC:

344

ESP6500AA

AF:

0.173

AC:

763

ESP6500EA

AF:

0.0769

AC:

661

ExAC

AF:

0.0792

AC:

9618

Asia WGS

AF:

0.0530

AC:

182

AN:

3478

EpiCase

AF:

0.0776

EpiControl

AF:

0.0750

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lethal Kniest-like syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Schwartz-Jampel syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.16

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.5

REVEL

Benign

0.053

Sift

Benign

0.40

Sift4G

Benign

0.11

Polyphen

0.091

Vest4

0.051

MPC

0.24

ClinPred

0.0015

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.061

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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