rs114015043

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS1

The NM_005529.7(HSPG2):c.12982G>A(p.Ala4328Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,613,698 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 14 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.51

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:

LDLRAD2 (HGNC:32071): (low density lipoprotein receptor class A domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LDLRAD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant where missense usually causes diseases, HSPG2

BP4

Computational evidence support a benign effect (MetaRNN=0.006559044).

BP6

Variant 1-21823637-C-T is Benign according to our data. Variant chr1-21823637-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 282934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21823637-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00252 (384/152286) while in subpopulation NFE AF= 0.00496 (337/68006). AF 95% confidence interval is 0.00452. There are 1 homozygotes in gnomad4. There are 172 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.12982G>A	p.Ala4328Thr	missense_variant	96/97	ENST00000374695.8
LDLRAD2	NM_001013693.3 linkuse as main transcript	c.*1422C>T		3_prime_UTR_variant	5/5	ENST00000344642.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8 linkuse as main transcript	c.12982G>A	p.Ala4328Thr	missense_variant	96/97	1	NM_005529.7	P1
LDLRAD2	ENST00000344642.7 linkuse as main transcript	c.*1422C>T		3_prime_UTR_variant	5/5	2	NM_001013693.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

384

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00495

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00233

AC:

585

AN:

250906

Hom.:

AF XY:

0.00260

AC XY:

353

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00436

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00357

AC:

5215

AN:

1461412

Hom.:

Cov.:

AF XY:

0.00351

AC XY:

2554

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00441

Gnomad4 OTH exome

AF:

0.00285

GnomAD4 genome

AF:

0.00252

AC:

384

AN:

152286

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00496

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00409

Hom.:

Bravo

AF:

0.00259

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00214

AC:

260

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HSPG2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The HSPG2 p.Ala4329Thr variant was not identified in the literature but was identified in dbSNP (ID: rs114015043), LOVD 3.0 and ClinVar (classified as uncertain significance by Illumina, as likely benign by EGL Genetic Diagnostics and Invitae, and as benign by Athena Diagnostics). The variant was identified in control databases in 653 of 282252 chromosomes (1 homozygous) at a frequency of 0.002314 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 551 of 128660 chromosomes (freq: 0.004283), Other in 17 of 7216 chromosomes (freq: 0.002356), Latino in 59 of 35424 chromosomes (freq: 0.001666), African in 14 of 24922 chromosomes (freq: 0.000562), South Asian in 8 of 30616 chromosomes (freq: 0.000261), European (Finnish) in 3 of 25104 chromosomes (freq: 0.00012) and Ashkenazi Jewish in 1 of 10362 chromosomes (freq: 0.000097), but was not observed in the East Asian population. The p.Ala4329 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2015	- -

Lethal Kniest-like syndrome

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

HSPG2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Schwartz-Jampel syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

Cadd

Benign

Dann

Benign

0.91

DEOGEN2

Benign

0.14

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.82

M_CAP

Benign

0.023

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.7

MutationTaster

Benign

0.76

N;D;D

PrimateAI

Benign

0.30

PROVEAN

Benign

1.6

REVEL

Benign

0.15

Sift

Benign

0.84

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.10

MVP

0.48

MPC

0.19

ClinPred

0.0049

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.43

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