1-21874505-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.3557G>A(p.Arg1186Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,613,214 control chromosomes in the GnomAD database, including 2,049 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. R1186W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.071 ( 742 hom., cov: 33)

Exomes 𝑓: 0.033 ( 1307 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0370

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 where missense usually causes diseases, HSPG2

BP4

Computational evidence support a benign effect (MetaRNN=0.0016741753).

BP6

Variant 1-21874505-C-T is Benign according to our data. Variant chr1-21874505-C-T is described in ClinVar as [Benign]. Clinvar id is 295860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21874505-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.3557G>A	p.Arg1186Gln	missense_variant	28/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HSPG2	ENST00000374695.8 linkuse as main transcript	c.3557G>A	p.Arg1186Gln	missense_variant	28/97	1	NM_005529.7	P1
HSPG2	ENST00000427897.1 linkuse as main transcript	c.122G>A	p.Arg41Gln	missense_variant	2/5	5
HSPG2	ENST00000498495.1 linkuse as main transcript	n.461G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0713

AC:

10847

AN:

152066

Hom.:

741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0401

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0318

Gnomad OTH

AF:

0.0694

GnomAD3 exomes

AF:

0.0343

AC:

8565

AN:

250006

Hom.:

337

AF XY:

0.0317

AC XY:

4291

AN XY:

135436

show subpopulations

Gnomad AFR exome

AF:

0.172

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0126

Gnomad FIN exome

AF:

0.0285

Gnomad NFE exome

AF:

0.0323

Gnomad OTH exome

AF:

0.0370

GnomAD4 exome

AF:

0.0331

AC:

48329

AN:

1461030

Hom.:

1307

Cov.:

AF XY:

0.0322

AC XY:

23426

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.187

Gnomad4 AMR exome

AF:

0.0235

Gnomad4 ASJ exome

AF:

0.0178

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0145

Gnomad4 FIN exome

AF:

0.0305

Gnomad4 NFE exome

AF:

0.0316

Gnomad4 OTH exome

AF:

0.0374

GnomAD4 genome

AF:

0.0714

AC:

10873

AN:

152184

Hom.:

742

Cov.:

AF XY:

0.0692

AC XY:

5145

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.179

Gnomad4 AMR

AF:

0.0401

Gnomad4 ASJ

AF:

0.0187

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.0261

Gnomad4 NFE

AF:

0.0318

Gnomad4 OTH

AF:

0.0687

Alfa

AF:

0.0363

Hom.:

293

Bravo

AF:

0.0760

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0345

AC:

133

ESP6500AA

AF:

0.174

AC:

768

ESP6500EA

AF:

0.0298

AC:

256

ExAC

AF:

0.0371

AC:

4500

Asia WGS

AF:

0.0170

AC:

AN:

3476

EpiCase

AF:

0.0296

EpiControl

AF:

0.0287

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Lethal Kniest-like syndrome

Benign:1

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. -

Schwartz-Jampel syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.080

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.085

MutationTaster

Benign

1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.54

REVEL

Benign

0.048

Sift

Benign

0.59

Sift4G

Benign

0.27

Polyphen

0.0020

Vest4

0.036

MPC

0.24

ClinPred

0.0031

GERP RS

0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.20

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