rs3736360

Positions:

chr1-21823627-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.12992G>A(p.Ser4331Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,611,800 control chromosomes in the GnomAD database, including 28,374 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S4331S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 1950 hom., cov: 33)

Exomes 𝑓: 0.19 ( 26424 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.00900

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 -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=0.040354222).

BP6

Variant 1-21823627-C-T is Benign according to our data. Variant chr1-21823627-C-T is described in ClinVar as [Benign]. Clinvar id is 295700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21823627-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 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.12992G>A	p.Ser4331Asn	missense_variant	96/97	ENST00000374695.8
LDLRAD2	NM_001013693.3 linkuse as main transcript	c.*1412C>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.12992G>A	p.Ser4331Asn	missense_variant	96/97	1	NM_005529.7	P1
LDLRAD2	ENST00000344642.7 linkuse as main transcript	c.*1412C>T		3_prime_UTR_variant	5/5	2	NM_001013693.3	P1

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23259

AN:

152080

Hom.:

1950

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0827

Gnomad AMI

AF:

0.0813

Gnomad AMR

AF:

0.131

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.176

Gnomad OTH

AF:

0.145

GnomAD3 exomes

AF:

0.181

AC:

45512

AN:

250946

Hom.:

4566

AF XY:

0.189

AC XY:

25708

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.0825

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.160

Gnomad SAS exome

AF:

0.285

Gnomad FIN exome

AF:

0.234

Gnomad NFE exome

AF:

0.179

Gnomad OTH exome

AF:

0.171

GnomAD4 exome

AF:

0.185

AC:

270255

AN:

1459600

Hom.:

26424

Cov.:

AF XY:

0.188

AC XY:

136605

AN XY:

726264

show subpopulations

Gnomad4 AFR exome

AF:

0.0820

Gnomad4 AMR exome

AF:

0.128

Gnomad4 ASJ exome

AF:

0.173

Gnomad4 EAS exome

AF:

0.172

Gnomad4 SAS exome

AF:

0.282

Gnomad4 FIN exome

AF:

0.235

Gnomad4 NFE exome

AF:

0.182

Gnomad4 OTH exome

AF:

0.182

GnomAD4 genome

AF:

0.153

AC:

23267

AN:

152200

Hom.:

1950

Cov.:

AF XY:

0.156

AC XY:

11625

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0827

Gnomad4 AMR

AF:

0.131

Gnomad4 ASJ

AF:

0.175

Gnomad4 EAS

AF:

0.166

Gnomad4 SAS

AF:

0.296

Gnomad4 FIN

AF:

0.241

Gnomad4 NFE

AF:

0.176

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.173

Hom.:

5562

Bravo

AF:

0.141

TwinsUK

AF:

0.186

AC:

688

ALSPAC

AF:

0.181

AC:

699

ESP6500AA

AF:

0.0869

AC:

383

ESP6500EA

AF:

0.176

AC:

1515

ExAC

AF:

0.184

AC:

22397

Asia WGS

AF:

0.243

AC:

843

AN:

3478

EpiCase

AF:

0.165

EpiControl

AF:

0.177

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lethal Kniest-like syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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: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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.15

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.53

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

MutationTaster

Benign

0.90

P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

0.060

REVEL

Benign

0.12

Sift

Benign

0.68

Sift4G

Benign

0.82

Polyphen

0.0010

Vest4

0.10

MPC

0.19

ClinPred

0.0026

GERP RS

2.0

Varity_R

0.24

gMVP

0.29

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