rs149159881

Positions:

chr1-21833291-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005529.7(HSPG2):c.11072C>T(p.Thr3691Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000792 in 1,614,134 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 6 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 4.72

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026100904).

BP6

Variant 1-21833291-G-A is Benign according to our data. Variant chr1-21833291-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 295725.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=5, Benign=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000663 (101/152316) while in subpopulation SAS AF= 0.00435 (21/4826). AF 95% confidence interval is 0.00292. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7 link	c.11072C>T	p.Thr3691Ile	missense_variant	80/97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HSPG2	ENST00000374695.8 link	c.11072C>T	p.Thr3691Ile	missense_variant	80/97	1	NM_005529.7	ENSP00000363827.3	P98160
HSPG2	ENST00000635682.1 link	c.203C>T	p.Thr68Ile	missense_variant	2/9	5		ENSP00000489161.1	A0A0U1RQT3
HSPG2	ENST00000471322.2 link	n.1427C>T		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00109

AC:

275

AN:

251370

Hom.:

AF XY:

0.00135

AC XY:

184

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00412

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000739

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000806

AC:

1178

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000986

AC XY:

717

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00364

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00394

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000560

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152316

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000559

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00114

AC:

138

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	HSPG2: BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2018	- -

Schwartz-Jampel syndrome;C1857100:Lethal Kniest-like syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2021

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

0.18

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.026

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.42

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0030

Polyphen

0.98

Vest4

0.63

MVP

0.80

MPC

0.74

ClinPred

0.042

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.72

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