chr1-21875662-C-T

Position:

chr1-21875662-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.3269G>A(p.Arg1090Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,602,974 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0060 ( 42 hom. )

Consequence

HSPG2
ENST00000374695.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.54

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=0.010121584).

BP6

Variant 1-21875662-C-T is Benign according to our data. Variant chr1-21875662-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 195883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21875662-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00363 (553/152314) while in subpopulation NFE AF= 0.006 (408/68020). AF 95% confidence interval is 0.00552. There are 1 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.3269G>A	p.Arg1090Gln	missense_variant	25/97	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.3269G>A	p.Arg1090Gln	missense_variant	25/97	1	NM_005529.7	ENSP00000363827	P1

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

553

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

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:

0.00600

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00456

AC:

1111

AN:

243406

Hom.:

AF XY:

0.00469

AC XY:

620

AN XY:

132328

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.00700

Gnomad NFE exome

AF:

0.00736

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00601

AC:

8717

AN:

1450660

Hom.:

Cov.:

AF XY:

0.00597

AC XY:

4312

AN XY:

722202

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00284

Gnomad4 FIN exome

AF:

0.00659

Gnomad4 NFE exome

AF:

0.00699

Gnomad4 OTH exome

AF:

0.00472

GnomAD4 genome

AF:

0.00363

AC:

553

AN:

152314

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

254

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00443

Gnomad4 NFE

AF:

0.00600

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00520

Hom.:

Bravo

AF:

0.00345

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00529

AC:

642

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00575

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

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
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	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 19, 2017	- -

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. -

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

0.063

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.0

DANN

Benign

0.87

DEOGEN2

Benign

0.24

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.79

M_CAP

Benign

0.016

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.55

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.98

REVEL

Benign

0.11

Sift

Benign

0.63

Sift4G

Benign

0.27

Polyphen

0.018

Vest4

0.081

MVP

0.44

MPC

0.27

ClinPred

0.0045

GERP RS

-0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.45

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