rs62618730

Positions:

chr1-21876363-T-G

Variant summary

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

The NM_005529.7(HSPG2):c.2869A>C(p.Asn957His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,613,118 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 53 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 59 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.00

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=0.0037935972).

BP6

Variant 1-21876363-T-G is Benign according to our data. Variant chr1-21876363-T-G is described in ClinVar as [Benign]. Clinvar id is 235713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21876363-T-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 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.2869A>C	p.Asn957His	missense_variant	23/97	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 linkuse as main transcript	c.2869A>C	p.Asn957His	missense_variant	23/97	1	NM_005529.7	ENSP00000363827	P1

Frequencies

GnomAD3 genomes

AF:

0.0148

AC:

2255

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0505

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00429

AC:

1060

AN:

247010

Hom.:

AF XY:

0.00316

AC XY:

423

AN XY:

133772

show subpopulations

Gnomad AFR exome

AF:

0.0561

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000438

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00180

AC:

2634

AN:

1460880

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1146

AN XY:

726620

show subpopulations

Gnomad4 AFR exome

AF:

0.0553

Gnomad4 AMR exome

AF:

0.00359

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000283

Gnomad4 OTH exome

AF:

0.00457

GnomAD4 genome

AF:

0.0149

AC:

2262

AN:

152238

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1032

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0505

Gnomad4 AMR

AF:

0.00758

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.00676

Hom.:

Bravo

AF:

0.0180

ESP6500AA

AF:

0.0583

AC:

257

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00522

AC:

634

Asia WGS

AF:

0.00289

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 27, 2020

- -

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. -

Lethal Kniest-like syndrome;C4551479:Schwartz-Jampel syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2022

- -

Schwartz-Jampel syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.34

Sift

Uncertain

0.024

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.35

MVP

0.74

MPC

0.27

ClinPred

0.038

GERP RS

2.6

Varity_R

0.13

gMVP

0.58

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

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