rs143736974

Positions:

chr1-21879108-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_005529.7(HSPG2):c.2357A>G(p.Asn786Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00694 in 1,614,212 control chromosomes in the GnomAD database, including 63 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 0.0061 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0070 ( 58 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 5.19

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 -12 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=0.012245119).

BP6

Variant 1-21879108-T-C is Benign according to our data. Variant chr1-21879108-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209161.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=6, Uncertain_significance=1}. Variant chr1-21879108-T-C is described in Lovd as [Likely_benign]. Variant chr1-21879108-T-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00607 (924/152340) while in subpopulation NFE AF= 0.00867 (590/68042). AF 95% confidence interval is 0.00809. There are 5 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.2357A>G	p.Asn786Ser	missense_variant	18/97	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 linkuse as main transcript	c.2357A>G	p.Asn786Ser	missense_variant	18/97	1	NM_005529.7	ENSP00000363827	P1
HSPG2	ENST00000480900.1 linkuse as main transcript			upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00606

AC:

923

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00867

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00621

AC:

1561

AN:

251436

Hom.:

AF XY:

0.00659

AC XY:

895

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00863

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.00826

Gnomad OTH exome

AF:

0.00831

GnomAD4 exome

AF:

0.00703

AC:

10283

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

5156

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.00765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00289

Gnomad4 FIN exome

AF:

0.0159

Gnomad4 NFE exome

AF:

0.00758

Gnomad4 OTH exome

AF:

0.00677

GnomAD4 genome

AF:

0.00607

AC:

924

AN:

152340

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

455

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0149

Gnomad4 NFE

AF:

0.00867

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00684

Hom.:

Bravo

AF:

0.00457

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00895

AC:

ExAC

AF:

0.00666

AC:

808

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	This variant is associated with the following publications: (PMID: 25504735) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	HSPG2: BP4, BS2 -

Schwartz-Jampel syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 30, 2015	This variant has been seen once in our laboratory in trans with another variant [T1639M] in a 37-year-old female with adult-onset myalgia, myotonia, intractable pain, stiffness, weakness, constipation. However, other individuals in our lab with this variant and additional HSPG2 variants (phase undetermined) have not had significant overlap with the syndrome, although if it predisposes to a milder adult-onset version, they may be too young for symptoms. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Lethal Kniest-like syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.012

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

2.9

MutationTaster

Benign

0.75

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.38

Sift

Benign

0.25

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.51

MVP

0.61

MPC

0.18

ClinPred

0.057

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.28

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