rs7355045

chr1-21845965-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005529.7(HSPG2):c.8464+143A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 979,460 control chromosomes in the GnomAD database, including 317,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.78 (46024 hom., cov: 32)
  • Exomes 𝑓: 0.81 (271703 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.41

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-21845965-T-C is Benign according to our data. Variant chr1-21845965-T-C is described in ClinVar as [Benign]. Clinvar id is 1245045.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPG2	NM_005529.7	c.8464+143A>G		intron_variant		ENST00000374695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPG2	ENST00000374695.8	c.8464+143A>G		intron_variant		1	NM_005529.7	P1

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117918 AN: 152070 Hom.: 45976 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.894

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.789

GnomAD4 exome AF: 0.809 AC: 669565 AN: 827274 Hom.: 271703 AF XY: 0.812 AC XY: 347087 AN XY: 427708

Gnomad4 AFR exome AF: 0.707

Gnomad4 AMR exome AF: 0.694

Gnomad4 ASJ exome AF: 0.891

Gnomad4 EAS exome AF: 0.839

Gnomad4 SAS exome AF: 0.812

Gnomad4 FIN exome AF: 0.816

Gnomad4 NFE exome AF: 0.815

Gnomad4 OTH exome AF: 0.807

GnomAD4 genome AF: 0.776 AC: 118021 AN: 152186 Hom.: 46024 Cov.: 32 AF XY: 0.774 AC XY: 57595 AN XY: 74400

Gnomad4 AFR AF: 0.701

Gnomad4 AMR AF: 0.709

Gnomad4 ASJ AF: 0.894

Gnomad4 EAS AF: 0.821

Gnomad4 SAS AF: 0.821

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.815

Gnomad4 OTH AF: 0.789

Alfa AF: 0.796 Hom.: 6001

Bravo AF: 0.766

Asia WGS AF: 0.828 AC: 2877 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	5.7
Dann	Benign	0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs7355045; hg19: chr1-22172458; COSMIC: COSV65970143; COSMIC: COSV65970143;