1-21873328-G-A

Position:

• chr1-21873328-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.3793+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 1,603,690 control chromosomes in the GnomAD database, including 559,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (45166 hom., cov: 32)
  • Exomes 𝑓: 0.84 (514232 hom.)
• Consequence: HSPG2 NM_005529.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0950

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-21873328-G-A is Benign according to our data. Variant chr1-21873328-G-A is described in ClinVar as [Benign]. Clinvar id is 1235752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPG2	NM_005529.7	c.3793+47C>T		intron_variant		ENST00000374695.8	NP_005520.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPG2	ENST00000374695.8	c.3793+47C>T		intron_variant		1	NM_005529.7	ENSP00000363827	P1
HSPG2	ENST00000427897.1	c.356+47C>T		intron_variant		5		ENSP00000397573

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114334 AN: 152024 Hom.: 45165 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.871

Gnomad EAS AF: 0.974

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.763

GnomAD3 exomes AF: 0.831 AC: 208892 AN: 251424 Hom.: 88350 AF XY: 0.829 AC XY: 112670 AN XY: 135902

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.977

Gnomad SAS exome AF: 0.734

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.849

Gnomad OTH exome AF: 0.839

GnomAD4 exome AF: 0.839 AC: 1217163 AN: 1451548 Hom.: 514232 Cov.: 29 AF XY: 0.836 AC XY: 604278 AN XY: 722914

Gnomad4 AFR exome AF: 0.471

Gnomad4 AMR exome AF: 0.904

Gnomad4 ASJ exome AF: 0.864

Gnomad4 EAS exome AF: 0.977

Gnomad4 SAS exome AF: 0.729

Gnomad4 FIN exome AF: 0.856

Gnomad4 NFE exome AF: 0.850

Gnomad4 OTH exome AF: 0.827

GnomAD4 genome AF: 0.752 AC: 114368 AN: 152142 Hom.: 45166 Cov.: 32 AF XY: 0.756 AC XY: 56231 AN XY: 74392

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.850

Gnomad4 ASJ AF: 0.871

Gnomad4 EAS AF: 0.974

Gnomad4 SAS AF: 0.734

Gnomad4 FIN AF: 0.866

Gnomad4 NFE AF: 0.852

Gnomad4 OTH AF: 0.764

Alfa AF: 0.830 Hom.: 73830

Bravo AF: 0.744

Asia WGS AF: 0.836 AC: 2905 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.82
CADD	Benign	2.5
DANN	Benign	0.59
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

Other links and lift over

dbSNP: rs2454290; hg19: chr1-22199821;