1-21885448-G-T

Position:

chr1-21885448-G-T

Variant summary

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

The NM_005529.7(HSPG2):c.1082C>A(p.Thr361Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,613,976 control chromosomes in the GnomAD database, including 41 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 0.0035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 41 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.55

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=0.009220779).

BP6

Variant 1-21885448-G-T is Benign according to our data. Variant chr1-21885448-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 193680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21885448-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00349 (531/152234) while in subpopulation NFE AF= 0.00578 (393/67990). AF 95% confidence interval is 0.00531. There are 0 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 41 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.1082C>A	p.Thr361Asn	missense_variant	10/97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8 linkuse as main transcript	c.1082C>A	p.Thr361Asn	missense_variant	10/97	1	NM_005529.7	ENSP00000363827.3		P98160

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

531

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00578

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00446

AC:

1120

AN:

251064

Hom.:

AF XY:

0.00460

AC XY:

625

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.00692

Gnomad NFE exome

AF:

0.00706

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00589

AC:

8610

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00586

AC XY:

4258

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00192

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00275

Gnomad4 FIN exome

AF:

0.00658

Gnomad4 NFE exome

AF:

0.00687

Gnomad4 OTH exome

AF:

0.00437

GnomAD4 genome

AF:

0.00349

AC:

531

AN:

152234

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

241

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000915

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00443

Gnomad4 NFE

AF:

0.00578

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00528

Hom.:

Bravo

AF:

0.00334

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00512

AC:

622

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00605

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	HSPG2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

Lethal Kniest-like syndrome

Benign:1

Likely 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 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

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 09, 2015

- -

HSPG2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2019

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 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.68

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.093

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.090

M_CAP

Benign

0.044

MetaRNN

Benign

0.0092

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.1

REVEL

Benign

0.25

Sift

Benign

0.069

Sift4G

Uncertain

0.019

Polyphen

0.61

Vest4

0.18

MVP

0.71

MPC

0.31

ClinPred

0.014

GERP RS

3.2

Varity_R

0.096

gMVP

0.31

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