1-21887634-A-G

Position:

chr1-21887634-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005529.7(HSPG2):c.744T>C(p.Leu248Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,613,516 control chromosomes in the GnomAD database, including 115,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L248L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.45 ( 16892 hom., cov: 32)

Exomes 𝑓: 0.36 ( 98748 hom. )

Consequence

HSPG2
NM_005529.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.84

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:

HSPG2 (HGNC:):

HSPG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 1-21887634-A-G is Benign according to our data. Variant chr1-21887634-A-G is described in ClinVar as [Benign]. Clinvar id is 295909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7 linkuse as main transcript	c.744T>C	p.Leu248Leu	synonymous_variant	8/97	ENST00000374695.8	NP_005520.4	P98160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HSPG2	ENST00000374695.8 linkuse as main transcript	c.744T>C	p.Leu248Leu	synonymous_variant	8/97	1	NM_005529.7	ENSP00000363827.3	P98160
HSPG2	ENST00000374673.4 linkuse as main transcript	c.549T>C	p.Leu183Leu	synonymous_variant	6/7	3		ENSP00000497688.1	A0A3B3IT11
HSPG2	ENST00000412328.5 linkuse as main transcript	n.512T>C		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes

AF:

0.449

AC:

68157

AN:

151792

Hom.:

16869

Cov.:

show subpopulations

Gnomad AFR

AF:

0.638

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.509

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.400

Gnomad FIN

AF:

0.357

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.336

Gnomad OTH

AF:

0.413

GnomAD3 exomes

AF:

0.419

AC:

104060

AN:

248518

Hom.:

23789

AF XY:

0.404

AC XY:

54285

AN XY:

134418

show subpopulations

Gnomad AFR exome

AF:

0.640

Gnomad AMR exome

AF:

0.579

Gnomad ASJ exome

AF:

0.253

Gnomad EAS exome

AF:

0.628

Gnomad SAS exome

AF:

0.404

Gnomad FIN exome

AF:

0.358

Gnomad NFE exome

AF:

0.334

Gnomad OTH exome

AF:

0.395

GnomAD4 exome

AF:

0.359

AC:

524289

AN:

1461606

Hom.:

98748

Cov.:

AF XY:

0.358

AC XY:

260001

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.646

Gnomad4 AMR exome

AF:

0.570

Gnomad4 ASJ exome

AF:

0.250

Gnomad4 EAS exome

AF:

0.596

Gnomad4 SAS exome

AF:

0.407

Gnomad4 FIN exome

AF:

0.365

Gnomad4 NFE exome

AF:

0.331

Gnomad4 OTH exome

AF:

0.374

GnomAD4 genome

AF:

0.449

AC:

68227

AN:

151910

Hom.:

16892

Cov.:

AF XY:

0.451

AC XY:

33474

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.638

Gnomad4 AMR

AF:

0.510

Gnomad4 ASJ

AF:

0.243

Gnomad4 EAS

AF:

0.631

Gnomad4 SAS

AF:

0.399

Gnomad4 FIN

AF:

0.357

Gnomad4 NFE

AF:

0.336

Gnomad4 OTH

AF:

0.411

Alfa

AF:

0.364

Hom.:

7283

Bravo

AF:

0.466

Asia WGS

AF:

0.499

AC:

1736

AN:

3478

EpiCase

AF:

0.325

EpiControl

AF:

0.311

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.54

DANN

Benign

0.90

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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