1-21842352-A-T

Position:

chr1-21842352-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_005529.7(HSPG2):c.8939T>A(p.Leu2980His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,609,560 control chromosomes in the GnomAD database, including 3,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 179 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2886 hom. )

Consequence

HSPG2
NM_005529.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.37

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=0.004461229).

BP6

Variant 1-21842352-A-T is Benign according to our data. Variant chr1-21842352-A-T is described in ClinVar as [Benign]. Clinvar id is 295765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.8939T>A	p.Leu2980His	missense_variant	68/97	ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8 linkuse as main transcript	c.8939T>A	p.Leu2980His	missense_variant	68/97	1	NM_005529.7	P1

Frequencies

GnomAD3 genomes

AF:

0.0405

AC:

6167

AN:

152102

Hom.:

177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00951

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.0343

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0586

Gnomad OTH

AF:

0.0458

GnomAD3 exomes

AF:

0.0490

AC:

12066

AN:

246234

Hom.:

423

AF XY:

0.0539

AC XY:

7208

AN XY:

133672

show subpopulations

Gnomad AFR exome

AF:

0.00839

Gnomad AMR exome

AF:

0.0237

Gnomad ASJ exome

AF:

0.0421

Gnomad EAS exome

AF:

0.000219

Gnomad SAS exome

AF:

0.105

Gnomad FIN exome

AF:

0.0441

Gnomad NFE exome

AF:

0.0568

Gnomad OTH exome

AF:

0.0514

GnomAD4 exome

AF:

0.0581

AC:

84728

AN:

1457340

Hom.:

2886

Cov.:

AF XY:

0.0601

AC XY:

43549

AN XY:

724330

show subpopulations

Gnomad4 AFR exome

AF:

0.00811

Gnomad4 AMR exome

AF:

0.0249

Gnomad4 ASJ exome

AF:

0.0426

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.109

Gnomad4 FIN exome

AF:

0.0450

Gnomad4 NFE exome

AF:

0.0603

Gnomad4 OTH exome

AF:

0.0540

GnomAD4 genome

AF:

0.0406

AC:

6175

AN:

152220

Hom.:

179

Cov.:

AF XY:

0.0401

AC XY:

2983

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00961

Gnomad4 AMR

AF:

0.0342

Gnomad4 ASJ

AF:

0.0401

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.0432

Gnomad4 NFE

AF:

0.0586

Gnomad4 OTH

AF:

0.0454

Alfa

AF:

0.0540

Hom.:

198

Bravo

AF:

0.0365

TwinsUK

AF:

0.0647

AC:

240

ALSPAC

AF:

0.0623

AC:

240

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0557

AC:

479

ExAC

AF:

0.0496

AC:

6024

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Lethal Kniest-like syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Schwartz-Jampel syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.26

DEOGEN2

Benign

0.066

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.024

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

2.3

REVEL

Benign

0.070

Sift

Benign

1.0

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.036

MPC

0.26

ClinPred

0.00051

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.26

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