NM_005529.7:c.5294-674A>G

Variant names:

• chr1-21858059-T-C
• rs4654991
• NM_005529.7:c.5294-674A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005529.7(HSPG2):​c.5294-674A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,152 control chromosomes in the GnomAD database, including 2,431 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2431 hom., cov: 32)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.999
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Schwartz-Jampel syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Silverman-Handmaker type dyssegmental dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Schwartz-Jampel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.5294-674A>G		intron_variant	Intron 42 of 96	ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.5294-674A>G		intron_variant	Intron 42 of 96	1	NM_005529.7	ENSP00000363827.3

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25465 AN: 152034 Hom.: 2429 Cov.: 32

Gnomad AFR AF: 0.0913

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.167 AC: 25477 AN: 152152 Hom.: 2431 Cov.: 32 AF XY: 0.170 AC XY: 12654 AN XY: 74370

African (AFR) AF: 0.0914 AC: 3795 AN: 41504

American (AMR) AF: 0.160 AC: 2443 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3468

East Asian (EAS) AF: 0.363 AC: 1877 AN: 5166

South Asian (SAS) AF: 0.342 AC: 1652 AN: 4824

European-Finnish (FIN) AF: 0.201 AC: 2131 AN: 10598

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12451 AN: 67994

Other (OTH) AF: 0.171 AC: 362 AN: 2114

Alfa AF: 0.178 Hom.: 4348

Bravo AF: 0.161

Asia WGS AF: 0.332 AC: 1151 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.69
DANN	Benign	0.69
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4654991; hg19: chr1-22184552;