rs112062179

Positions:

chr1-21833508-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000374695.8(HSPG2):c.10937G>A(p.Arg3646His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,614,092 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3646C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 13 hom. )

Consequence

HSPG2
ENST00000374695.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.573

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=0.012715757).

BP6

Variant 1-21833508-C-T is Benign according to our data. Variant chr1-21833508-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 198680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21833508-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00296 (450/152236) while in subpopulation NFE AF= 0.00479 (326/68010). AF 95% confidence interval is 0.00437. There are 4 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.10937G>A	p.Arg3646His	missense_variant	79/97	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HSPG2	ENST00000374695.8 linkuse as main transcript	c.10937G>A	p.Arg3646His	missense_variant	79/97	1	NM_005529.7	ENSP00000363827	P1
HSPG2	ENST00000635682.1 linkuse as main transcript	c.71G>A	p.Arg24His	missense_variant	1/9	5		ENSP00000489161
HSPG2	ENST00000471322.2 linkuse as main transcript	n.1292G>A		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

450

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00479

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00315

AC:

792

AN:

251276

Hom.:

AF XY:

0.00311

AC XY:

423

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.00434

Gnomad NFE exome

AF:

0.00494

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00453

AC:

6618

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

3189

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00230

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00187

Gnomad4 FIN exome

AF:

0.00461

Gnomad4 NFE exome

AF:

0.00526

Gnomad4 OTH exome

AF:

0.00368

GnomAD4 genome

AF:

0.00296

AC:

450

AN:

152236

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

182

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.00479

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00462

Hom.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00344

AC:

418

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	HSPG2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 27, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 22, 2015

- -

HSPG2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Benign

0.10

Eigen_PC

Benign

0.014

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.76

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.38

Sift

Benign

0.047

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.19

MVP

0.72

MPC

0.27

ClinPred

0.021

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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