rs897471

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.4508C>T(p.Ala1503Val) variant causes a missense change. The variant allele was found at a frequency of 0.717 in 1,599,188 control chromosomes in the GnomAD database, including 413,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1503A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.70 ( 38067 hom., cov: 34)

Exomes 𝑓: 0.72 ( 375403 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.32

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2454389E-6).

BP6

Variant 1-21864961-G-A is Benign according to our data. Variant chr1-21864961-G-A is described in ClinVar as [Benign]. Clinvar id is 291236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21864961-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.4508C>T	p.Ala1503Val	missense_variant	Exon 36 of 97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 link	c.4508C>T	p.Ala1503Val	missense_variant	Exon 36 of 97	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.704

AC:

107084

AN:

152058

Hom.:

38063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.613

Gnomad AMI

AF:

0.751

Gnomad AMR

AF:

0.771

Gnomad ASJ

AF:

0.752

Gnomad EAS

AF:

0.886

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.736

Gnomad MID

AF:

0.801

Gnomad NFE

AF:

0.732

Gnomad OTH

AF:

0.713

GnomAD3 exomes

AF:

0.732

AC:

160466

AN:

219192

Hom.:

59344

AF XY:

0.724

AC XY:

86840

AN XY:

119962

show subpopulations

Gnomad AFR exome

AF:

0.612

Gnomad AMR exome

AF:

0.807

Gnomad ASJ exome

AF:

0.744

Gnomad EAS exome

AF:

0.892

Gnomad SAS exome

AF:

0.577

Gnomad FIN exome

AF:

0.750

Gnomad NFE exome

AF:

0.735

Gnomad OTH exome

AF:

0.750

GnomAD4 exome

AF:

0.718

AC:

1039393

AN:

1447012

Hom.:

375403

Cov.:

AF XY:

0.715

AC XY:

514172

AN XY:

719032

show subpopulations

Gnomad4 AFR exome

AF:

0.605

Gnomad4 AMR exome

AF:

0.802

Gnomad4 ASJ exome

AF:

0.738

Gnomad4 EAS exome

AF:

0.888

Gnomad4 SAS exome

AF:

0.575

Gnomad4 FIN exome

AF:

0.742

Gnomad4 NFE exome

AF:

0.722

Gnomad4 OTH exome

AF:

0.720

GnomAD4 genome

AF:

0.704

AC:

107117

AN:

152176

Hom.:

38067

Cov.:

AF XY:

0.706

AC XY:

52535

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.612

Gnomad4 AMR

AF:

0.772

Gnomad4 ASJ

AF:

0.752

Gnomad4 EAS

AF:

0.886

Gnomad4 SAS

AF:

0.568

Gnomad4 FIN

AF:

0.736

Gnomad4 NFE

AF:

0.732

Gnomad4 OTH

AF:

0.711

Alfa

AF:

0.734

Hom.:

75360

Bravo

AF:

0.704

TwinsUK

AF:

0.705

AC:

2613

ALSPAC

AF:

0.717

AC:

2762

ESP6500AA

AF:

0.620

AC:

2716

ESP6500EA

AF:

0.740

AC:

6349

ExAC

AF:

0.706

AC:

84444

Asia WGS

AF:

0.700

AC:

2434

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal Kniest-like syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Schwartz-Jampel syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Sep 20, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.0024

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.15

Sift

Benign

0.056

Sift4G

Uncertain

0.031

Polyphen

1.0

Vest4

0.11

MPC

0.33

ClinPred

0.020

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.52

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